bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of cardiac autonomic modulation during graded head-up tilt by symbolic analysis of heart rate variability
Authors: Porta Alberto , Tobaldini Eleonora , Guzzetti Stefano , Furlan Raffaello , Montano Nicola , Gnecchi-Ruscone Tomaso
Published: February 2007

Two symbolic indexes, the percentage of sequences characterized by three heart periods with no significant variations (0V%) and that with two significant unlike variations (2UV%), have been found to reflect changes in sympathetic and vagal modulations, respectively. We tested the hypothesis that symbolic indexes may track the gradual shift of the cardiac autonomic modulation during an incremental head-up tilt test. Symbolic analysis was carried out over heart period variability series (250 cardiac beats) derived from ECG recordings during a graded head-up tilt test (0, 15, 30, 45, 60, 75, and 90°) in 17 healthy subjects. The percentage of subjects showing a significant linear correlation (Spearman rank-order correlation) with tilt angles was utilized to evaluate the performance of symbolic analysis. Spectral analysis was carried out for comparison over the same series. 0V% progressively increased with tilt angles, whereas 2UV% gradually decreased. The decline of 2UV% was greater than the increase of 0V% at low tilt angles. Linear correlation with tilt angles was exhibited in a greater percentage of subjects for 0V% and 2UV% than for any spectral index. Our findings suggest that symbolic analysis performed better than spectral analysis and, thus, is a suitable methodology for assessment of the subtle changes of cardiac autonomic modulation induced by a graded head-up tilt test. Moreover, symbolic analysis indicates that the changes of cardiac sympathetic and vagal modulations observed during this protocol were reciprocal but characterized by different absolute magnitudes.
Impaired central hemodynamic response and exaggerated vasoconstriction during muscle metaboreflex activation in heart failure patients
Authors: Crisafulli Antonio , Salis Enrico , Tocco Filippo , Melis Franco , Milia Raffaele , Pittau Gianluigi , Caria Marcello A. , Solinas Roberto , Meloni Luigi , Pagliaro Pasquale , Concu Alberto
Published: February 2007

The muscle metaboreflex is enhanced in chronic heart failure (CHF) patients, and this fact has been associated with the early fatigue shown by these patients in response to exercise. In animal studies of CHF, it was found that the limited capacity to enhance ventricular performance is responsible for a functional shift from a cardiac output to a systemic vascular resistance (SVR) increase in the mechanism by which the cardiovascular system raises blood pressure in response to the metaboreflex. However, the existence of this functional shift is still unknown in humans. The present study was undertaken to test the hypothesis that a similar hemodynamic response was also present in humans with CHF. The hemodynamic response to metaboreflex activation obtained through postexercise ischemia was assessed in nine patients with CHF and nine healthy controls (CTL) by means of impedance cardiography. The main results were that 1) the blood pressure rise due to the metaboreflex was similar in the two groups; 2) the CTL group achieved the blood pressure response via cardiac output increase, and the CHF group, via SVR increase; and 3) stroke volume was enhanced in the CTL group and decreased in the CHF group. This study demonstrates that in CHF patients, metaboreflex recruitment causes a functional shift from flow increase to peripheral vasoconstriction in the mechanism through which blood pressure is increased. The incapacity to enhance cardiac performance and stroke volume is probably the primary cause of this cardiovascular alteration.
Contribution of anaerobic metabolism to reactive hyperemia in skeletal muscle
Authors: Tóth András , Pal Miklos , Intaglietta Marcos , Johnson Paul C.
Published: February 2007

Elevated blood flow (reactive hyperemia) is seen in many organs after a period of blood flow stoppage. This hyperemia is often considered to be due in part to a shift to anaerobic metabolism during tissue hypoxia. The aim of our study was to test this hypothesis in skeletal muscle. For this purpose we measured NADH fluorescence at localized tissue areas in cat sartorius muscle during and after arterial occlusions of 5–300 s. In parallel studies, red blood cell (RBC) velocity was measured in venules. Tissue NADH fluorescence rose significantly with occlusions of 45 s or greater, reaching a maximum of 44% above control at 180 s. Peak RBC velocity rose to four times control as occlusion duration was increased from 5 to 45 s, but hyperemia duration was stable at ∼70 s. With occlusions of 45–240 s, hyperemia duration increased progressively to 210 s while peak flow was unchanged. However, after 300-s occlusions, peak flow rose to six times above control and hyperemia duration fell to 140 s. With occlusions of 45–300 s the time integral both of increased NADH fluorescence and of reduced fluorescence following occlusion release showed a high degree of correlation with the additional hyperemia. We conclude that in this muscle anaerobic vasodilator metabolites are responsible for the increase in reactive hyperemia with arterial occlusions longer than 45 s. Since the durations of reactive hyperemia and reduced fluorescence are substantially different, vasodilator metabolite removal may be due to washout by the bloodstream rather than metabolic uptake.
Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure
Authors: Brower Gregory L. , Levick Scott P. , Janicki Joseph S.
Published: February 2007

Angiotensin-converting enzyme (ACE) inhibitors represent the front-line pharmacological treatment of heart failure, which is characterized by left ventricular (LV) dilatation and inappropriate hypertrophy. The mechanism of action of ACE inhibitors is still unclear, but evidence suggests that they may act by influencing matrix metalloproteinase (MMP) activity. This study sought to determine whether ACE inhibitors can directly regulate MMP activity and whether this results in positive structural and functional adaptations to the heart. To this end, MMP-2 activity in LV tissue extracted from rats with an aortocaval (AV) fistula was assessed by in vitro incubation as well as in vivo treatment with captopril, lisinopril, or quinapril. Furthermore, LV size and function were determined in untreated AV fistula rats, AV fistula rats treated with lisinopril (3, 5, and 8 wk), and age-matched sham-operated controls. In vitro incubation with captopril, lisinopril, or quinapril significantly reduced MMP-2 activity, as did in vivo treatment. This occurred without a reduction in the available pool of MMP-2 protein. Long-term in vivo administration of lisinopril also prevented LV dilatation, attenuated myocardial hypertrophy, and prevented changes in myocardial compliance and contractility. The results herein demonstrate that ACE inhibitors prevent MMP-2 activity and, in so doing, represent a mechanism responsible for preventing the negative structural and functional changes that occur in the rat AV fistula model of heart failure.
Effects of fluid shear stress on adventitial fibroblast migration: implications for flow-mediated mechanisms of arterialization and intimal hyperplasia
Authors: Garanich Jeffrey S. , Mathura Rishi A. , Shi Zhong-Dong , Tarbell John M.
Published: February 2007

The involvement of vascular fibroblasts (FBs) and smooth muscle (SM)-like cells in physiological and pathological processes in large vessels (intimal hyperplasia) and microvessels (capillary arterialization), and the realization that these cells are exposed to interstitial flow shear stress (SS), motivate this study of SS on FB migratory activity. Rat adventitial FBs were grown to either 30–50% confluence (subconfluent FBs; SFBs) or full confluence (confluent FBs; CFBs) in culture. Immunofluorescence and Western blotting assays were conducted to evaluate the expression of two phenotype markers: SM α-actin and SM myosin heavy chain (MHC). Both assays indicated a significant increase in SM α-actin expression in CFBs compared with SFBs, suggesting a phenotype difference between the two cell populations. SFBs and CFBs both expressed minimal SM MHC. Both cell populations were seeded on Matrigel-coated cell culture inserts and exposed to 4 h of either 1 or 20 dyn/cm2 SS via a rotating disk apparatus in the presence of the chemoattractant platelet-derived growth factor-BB to quantify the effect of SS on SFB and CFB migration. Four hours of 20 dyn/cm2 SS significantly enhanced SFB migration while it suppressed CFB migratory activity. Four hours of 1 dyn/cm2 SS did not significantly alter either SFB or CFB migration levels. Because of the distinct migratory responses of SFBs and CFBs in response to SS, phenotype modulation appears to be one way to regulate their involvement in both physiological and pathological remodeling processes.
Cardioprotection by adenosine A2Aagonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia
Authors: Glover David K. , Ruiz Mirta , Takehana Kazuya , Petruzella Frank D. , Rieger Jayson M. , Macdonald Timothy L. , Watson Denny D. , Linden Joel , Beller George A.
Published: February 2007

We sought to determine whether administration of a very low, nonvasodilating dose of a highly selective adenosine A2Areceptor agonist (ATL-193 or ATL-146e) would be cardioprotective in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Twenty-four anesthetized open-chest dogs underwent either 4 ( n = 12) or 10 cycles ( n = 12) of 5-min left anterior descending coronary artery (LAD) occlusions interspersed by 5 or 10 min of reperfusion. Left ventricular thickening was measured from baseline through 180 min after the last occlusion-reperfusion cycle. Regional flow was measured with microspheres. In 12 of 24 dogs, A2Areceptor agonist was infused intravenously beginning 2 min prior to the first occlusion and continuing throughout reperfusion at a dose below that which produces vasodilatation (0.01 μg·kg−1·min−1). Myocardial flow was similar between control and A2Areceptor agonist-treated animals, confirming the absence of A2receptor agonist-induced vasodilatation. During occlusion, there was severe dyskinesis with marked LAD zone thinning in all animals. After 180 min of reperfusion following the last cycle, significantly greater recovery of LAD zone thickening was observed in A2Areceptor agonist-treated vs. control animals in both the 4-cycle (91 ± 7 vs. 56 ± 12%, respectively; P < 0.05) and the 10-cycle (65 ± 9 vs. 8 ± 16%, respectively; P < 0.05) occlusion groups. The striking amount of functional recovery observed with administration of low, nonvasodilating doses of adenosine A2Aagonist ATL-193 or ATL-146e supports their further evaluation for the attenuation of postischemic stunning in the clinical setting.
Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow
Authors: Ghorishi Zahra , Milstein Jay M. , Poulain Francis R. , Moon-Grady Anita , Tacy Theresa , Bennett Stephen H. , Fineman Jeffery R. , Eldridge Marlowe W.
Published: February 2007

Congenital heart disease with increased blood flow commonly leads to the development of increased pulmonary vascular reactivity and pulmonary arterial hypertension by mechanisms that remain unclear. We hypothesized a shear stress paradigm of hemodynamic reactivity and network remodeling via the persistence and/or exacerbation of a fetal diameter bifurcation phenotype [parent diameter d0and daughters d1≥ d2with α < 2 in ( d1/ d0)α+ ( d2/ d0)αand area ratio β < 1 in β = ( d12+ d22)/ d02] that mechanically acts as a high resistance magnifier/shear stress amplifier to blood flow. Evidence of a hemodynamic influence on network remodeling was assessed with a lamb model of high-flow-induced secondary pulmonary hypertension in which an aortopulmonary graft was surgically placed in one twin in utero (Shunt twin) but not in the other (Control twin). Eight weeks after birth arterial casts were made of the left pulmonary arterial circulation. Bifurcation diameter measurements down to 0.010 mm in the Shunt and Control twins were then compared with those of an unoperated fetal cast. Network organization, cumulative resistance, and pressure/shear stress distributions were evaluated via a fractal model whose dimension D0≈ α delineates hemodynamic reactivity. Fetus and Control twin D0differed: fetus D0= 1.72, a high-resistance/shear stress amplifying condition; control twin D0= 2.02, an area-preserving transport configuration. The Shunt twin ( D0= 1.72) maintained a fetal design but paradoxically remodeled diameter geometry to decrease cumulative resistance relative to the Control twin. Our results indicate that fetal/neonatal pulmonary hemodynamic reactivity remodels in response to shear stress, but the response to elevated blood flow and pulmonary hypertension involves the persistence and exacerbation of a fetal diameter bifurcation phenotype that facilitates endothelial dysfunction/injury.
Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress
Authors: Colgan Olga C. , Ferguson Gail , Collins Nora T. , Murphy Ronan P. , Meade Gerardeane , Cahill Paul A. , Cummins Philip M.
Published: February 2007

Blood-brain barrier (BBB) controls paracellular solute diffusion into the brain microenvironment and is maintained primarily by tight junctions between adjacent microvascular endothelial cells. Studies implicate blood flow-associated shear stress as a pathophysiological mediator of BBB function, although detailed biochemical data are scarce. We hypothesize that shear stress upregulates BBB function via direct modulation of expression and properties of pivotal tight-junction proteins occludin and zonula occludens-1 (ZO-1). Bovine brain microvascular endothelial cells (BBMvECs) were exposed to either steady or pulsatile shear stress (10 and 14 dyn/cm2, respectively) for 24 h. Sheared BBMvECs were monitored for occludin-ZO-1 expression, association, and subcellular localization, and transendothelial permeability of BBMvECs to FITC-dextran and14[C]sucrose was assessed. Actin reorganization and BBMvEC realignment were observed following steady shear stress for 24 h. Substantial increases in occludin mRNA and protein expression (2.73 ± 0.26- and 1.83 ± 0.03-fold) and in occludin-ZO-1 association (2.12 ± 0.15-fold) were also observed. Steady shear stress also induced clear relocalization of both proteins to the cell-cell border in parallel with reduced transendothelial permeability to FITC-dextran (but not sucrose). Following pulsatile shear stress, increased protein levels for both occludin and ZO-1 (2.15 ± 0.02- and 1.67 ± 0.21-fold) and increased occludin-ZO-1 association (2.91 ± 0.14-fold) were observed in parallel with a reduction in transendothelial permeability to14[C]sucrose. Shear stress upregulates BBMvEC barrier function at the molecular level via modulation of expression, association, and localization of occludin and ZO-1. The pulsatile shear model appeared to give the most profound biochemical responses.
Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1–7) in transgenic Ren-2 hypertensive rats
Authors: Trask Aaron J. , Averill David B. , Ganten Detlev , Chappell Mark C. , Ferrario Carlos M.
Published: February 2007

Angiotensin-converting enzyme-2 (ACE2) converts angiotensin II (ANG II) to angiotensin-(1–7) [ANG-(1–7)], and this enzyme may serve as a key regulatory juncture in various tissues. Although the heart expresses ACE2, the extent that the enzyme participates in the cardiac processing of ANG II and ANG-(1–7) is equivocal. Therefore, we utilized the Langendorff preparation to characterize the ACE2 pathway in isolated hearts from male normotensive Sprague-Dawley [Tg(−)] and hypertensive [mRen2]27 [Tg(+)] rats. During a 60-min recirculation period with 10 nM ANG II, the presence of ANG-(1–7) was assessed in the cardiac effluent. ANG-(1–7) generation from ANG II was similar in both the normal and hypertensive hearts [Tg(−): 510 ± 55 pM, n = 20 vs. Tg(+): 497 ± 63 pM, n = 14] with peak levels occurring at 30 min after administration of the peptide. ACE2 inhibition (MLN-4760, 1 μM) significantly reduced ANG-(1–7) production by 83% (57 ± 19 pM, P < 0.01, n = 7) in the Tg(+)rats, whereas the inhibitor had no significant effect in the Tg(−)rats (285 ± 53 pM, P > 0.05, n = 10). ACE2 activity was found in the effluent of perfused Tg(−)and Tg(+)hearts, and it was highly associated with ACE2 protein expression ( r = 0.78). This study is the first demonstration for a direct role of ACE2 in the metabolism of cardiac ANG II in the hypertrophic heart of hypertensive rats. We conclude that predominant expression of cardiac ACE2 activity in the Tg(+)may be a compensatory response to the extensive cardiac remodeling in this strain.
Effects of hypertension on cardiovascular responses to epinephrine in humans
Authors: Leenen Frans H. H. , Fourney Anne , Coletta Elizabeth , White Roselyn
Published: February 2007

Cardiac β-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation.
Angiotensin II mediates postischemic leukocyte-endothelial interactions: role of calcitonin gene-related peptide
Authors: Yusof Mozow , Kamada Kazuhiro , Spencer Gaskin F. , Korthuis Ronald J.
Published: February 2007

Vascular inflammation and enhanced production of angiotensin II (ANG II) are involved in the pathogenesis of hypertension and diabetes, disease states that predispose the afflicted individuals to ischemic disorders. In light of these observations, we postulated that ANG II may play a role in promoting leukocyte rolling (LR) and adhesion (LA) in postcapillary venules after exposure of the small intestine to ischemia-reperfusion (I/R). Using an intravital microscopic approach in C57BL/6J mice, we showed that ANG II type I (AT1) or type II (AT2) receptor antagonism (with valsartan or PD-123319, respectively), inhibition of angiotensin-converting enzyme (ACE) with captopril, or calcitonin gene-related peptide (CGRP) receptor blockade (CGRP8-37) prevented postischemic LR but did not influence I/R-induced LA. However, both postischemic LR and LA were largely abolished by concomitant AT1and AT2receptor blockade or chymase inhibition (with Y-40079). Additionally, exogenously administered ANG II increased LR and LA, effects that were attenuated by pretreatment with a CGRP receptor antagonist or an NADPH oxidase inhibitor (apocynin). Our work suggests that ANG II, formed by the enzymatic activity of ACE and chymase, plays an important role in inducing postischemic LR and LA, effects that involve the engagement of both AT1and AT2receptors and may be mediated by CGRP and NADPH oxidase.
Activity of the β-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism
Authors: Giger Julia , Qin Anqi X. , Bodell Paul W. , Baldwin Kenneth M. , Haddad Fadia
Published: February 2007

Two genes encoding cardiac myosin heavy chain (MHC) isoforms, β and α, are arranged in tandem 4.5 kb apart. We examined pre-mRNA and mature mRNA levels of β and α genes in control, diabetic (streptozotocin), hypothyroid (propylthiouracil), and hyperthyroid rat hearts and analyzed the naturally occurring antisense (AS) β RNA species that starts in the middle of the 4.5-kb intergenic region and extends upstream to the β-gene promoter. The β and α genes are expressed antithetically in control, diabetic, hypothyroid, and hyperthyroid hearts. Expression of AS β-RNA was positively correlated with α-mRNA and negatively correlated with sense β mRNA. These results support the novel idea of common promoter-regulatory elements situated in the intergenic region that likely control transcription of both sense α and AS β genes and that AS β transcription negatively regulates β-MHC gene expression. To test whether an intergenic promoter drives transcription of AS β RNA, a 1340-bp sequence of the intergenic region was inserted into a luciferase plasmid in the 3′-to-5′ AS direction and was injected into rat ventricle. This promoter was activated in control heart and decreased greatly in response to propylthiouracil and streptozotocin and increased in hyperthyroid rats, similar in pattern to the endogenous AS β RNA. When a putative retinoic acid receptor (RAR) site (a known thyroid hormone receptor cofactor) in this promoter was mutated, the reporter activity was almost abolished in control, propylthiouracil, and streptozotocin hearts. We conclude that there is an intergenic promoter that is active in the AS direction and that the putative RAR element is a vital regulatory site.
Live imaging of collagen remodeling during angiogenesis
Authors: Kirkpatrick Nathaniel D. , Andreou Stylianos , Hoying James B. , Utzinger Urs
Published: February 2007

To better understand interstitial matrix remodeling during angiogenesis, we probed endogenous optical signatures of collagen fibrils and cells with multiphoton microscopy to noninvasively visualize, in real-time, changes to fibril organization around angiogenic sprouts and growing neovessels. From analyses of the second-harmonic generation signal from fibrillar collagen and two-photon excited fluorescence, as well as coherent transmitted light from vascular cells, we found that microvessel fragments interacting with the collagen matrix exhibited two key features: a strong association of fibrillar collagen around the parent vessel fragment during vessel construct reconstitution and a substantial collagen fibril reorganization by sprout and neovessel tips. Results indicate that angiogenic sprouts and growing neovessels actively and differentially remodel existing collagen fibrils. This imaging approach to assess local changes in matrix organization may have a broader impact on tissue biology and mechanics during angiogenesis and allow for new insights in cardiovascular, diabetes, and cancer research.
Lactate interferes with ATP release from red blood cells
Authors: Rozier Michael D. , Zata Vincent J. , Ellsworth Mary L.
Published: February 2007

Upon exposure to low Po2, the red blood cells of most species, including humans, release increased amounts of ATP that ultimately serves as a regulator of vascular tone matching oxygen supply with demand. In pathological conditions such as malaria and sepsis, a maldistribution of perfusion exists with its severity often correlated with the extent of elevation of serum lactate frequently in the absence of an alteration in pH. We hypothesized that the increased levels of lactate might impair the ability of red blood cells to appropriately respond to conditions of low Po2, thus preventing its important blood flow regulatory role. Using an in vitro system and rabbit red blood cells, we evaluated the capacity of cells incubated with lactate to release increased amounts of ATP in response to acute exposure to low Po2. We found that in the presence of lactate, the red blood cells did not release ATP. However, when sodium dichloroacetate, a drug used clinically to lower blood lactate levels, was added, ATP release was restored to levels that were not different from that of control cells (no lactate), even though intracellular levels of ATP were not. These results support the presence of a distinct flow regulatory pool of ATP within the red blood cell that can be independently regulated, and that lactate interferes with the ATP production within this pool, thereby diminishing the amount of ATP available for release on exposure to low Po2. Therefore, if lactate levels can be reduced, the vascular regulatory capacity of the red blood cell should be restored, thus enabling the appropriate matching of oxygen supply with oxygen demand.
Nitrite-dependent vasodilation is facilitated by hypoxia and is independent of known NO-generating nitrite reductase activities
Authors: Dalsgaard Thomas , Simonsen Ulf , Fago Angela
Published: February 2007

The reduction of circulating nitrite to nitric oxide (NO) has emerged as an important physiological reaction aimed to increase vasodilation during tissue hypoxia. Although hemoglobin, xanthine oxidase, endothelial NO synthase, and the bc1complex of the mitochondria are known to reduce nitrite anaerobically in vitro, their relative contribution to the hypoxic vasodilatory response has remained unsolved. Using a wire myograph, we have investigated how the nitrite-dependent vasodilation in rat aortic rings is controlled by oxygen tension, norepinephrine concentration, soluble guanylate cyclase (the target for vasoactive NO), and known nitrite reductase activities under hypoxia. Vasodilation followed overall first-order dependency on nitrite concentration and, at low oxygenation and norepinephrine levels, was induced by low-nitrite concentrations, comparable to those found in vivo. The vasoactive effect of nitrite during hypoxia was abolished on inhibition of soluble guanylate cyclase and was unaffected by removal of the endothelium or by inhibition of xanthine oxidase and of the mitochondrial bc1complex. In the presence of hemoglobin and inositol hexaphosphate (which increases the fraction of deoxygenated heme), the effect of nitrite was not different from that observed with inositol hexaphosphate alone, indicating that under the conditions investigated here deoxygenated hemoglobin did not enhance nitrite vasoactivity. Together, our results indicate that the mechanism for nitrite vasorelaxation is largely intrinsic to the vessel and that under hypoxia physiological nitrite concentrations are sufficient to induce NO-mediated vasodilation independently of the nitrite reductase activities investigated here. Possible reaction mechanisms for nitrite vasoactivity, including formation of S-nitrosothiols within the arterial smooth muscle, are discussed.
Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth
Authors: Rocic Petra , Kolz Christopher , Reed Ryan , Potter Barry , Chilian William M.
Published: February 2007

Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 ± 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 ± 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 ± 4% of normal zone). Similar results were obtained with apocynin following RI (32 ± 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 ± 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 ± 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.
Apoptotic signaling induces hyperpermeability following hemorrhagic shock
Authors: Childs Ed W. , Tharakan Binu , Hunter Felicia A. , Tinsley John H. , Cao Xiaobo
Published: February 2007

Hemorrhagic shock (HS) disrupts the endothelial cell barrier, resulting in microvascular hyperpermeability. Recent studies have also demonstrated that activation of the apoptotic signaling cascade is involved in endothelial dysfunction, which may result in hyperpermeability. Here we report involvement of the mitochondrial “intrinsic” pathway in microvascular hyperpermeability following HS in rats. HS resulted in the activation of the mitochondrial intrinsic pathway, as is evident from an increase in the proapoptotic Bcl-2 family member BAK, release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. This, along with the in vivo transfection of the proapoptotic peptide BAK (BH3), resulted in hyperpermeability (as visualized by intravital microscopy), release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. Conversely, transfection of the BAK (BH3) mutant had no effect on hyperpermeability. Together, these results demonstrate involvement of the mitochondrial intrinsic apoptotic pathway in HS-induced hyperpermeability and that the attenuation of this pathway may provide an alternative strategy in preserving vascular barrier integrity.
HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway
Authors: Gupta Sanjiv , Knowlton A. A.
Published: February 2007

The heat shock proteins (HSP) are a highly conserved family of proteins with critical functions in protein folding, protein trafficking, and cell signaling. These proteins also protect the cell against injury. HSP60 has been found in the extracellular space and has been identified in the plasma of some individuals. HSP60 is thought to be a “danger signal” to the immune system and is also highly immunogenic. Thus extracellular HSP60 is possibly toxic to the cell. The mechanism by which HSP60 is released into the extracellular space is unknown, as is whether it is released by cardiac myocytes. We investigated several different pathways controlling protein release including the classic, Golgi-mediated pathway. We found that HSP60 is released via exosomes, and that within the exosome, HSP60 is tightly attached to the exosome membrane.
Absence of diastolic mitral annular oscillations is a marker for relaxation-related diastolic dysfunction
Authors: Riordan Matt M. , Kovács Sándor J.
Published: February 2007

Although Doppler tissue imaging frequently indicates the presence of mitral annular oscillations (MAO) following the E′ wave (E″ wave, etc.), only recently was it shown that annular “ringing” follows the rules of damped harmonic oscillatory motion. Oscillatory model-based analysis of E′ and E″ waves provides longitudinal left ventricular (LV) stiffness ( k′), relaxation/viscoelasticity ( c′), and stored elastic strain ( xo′) parameters. We tested the hypothesis that presence (MAO+) vs. absence (MAO−) of diastolic MAO is an index of superior LV relaxation by analyzing simultaneous echocardiographic-hemodynamic data from 35 MAO+and 20 MAO−normal ejection fraction (EF) subjects undergoing cardiac catheterization. Echocardiographic annular motion and transmitral flow data were analyzed with a previously validated kinematic model of filling. Invasive and noninvasive diastolic function (DF) indexes differentiated between MAO+and MAO−groups. Specifically, the MAO+group had a shorter time constant of isovolumic relaxation [τ; 51 (SD 13) vs. 67 (SD 27) ms; P < 0.01] and isovolumic relaxation time [63 (SD 16) vs. 82 (SD 17) ms; P < 0.001] and greater ratio of peak E-wave to peak A-wave velocity [1.19 (SD 0.31) vs. 0.97 (SD 0.31); P < 0.05]. The MAO+group had greater peak lateral mitral annulus velocity [E′; 17.5 (SD 3.1) vs. 13.5 (SD 3.8) cm/s; P < 0.001] and LVEF [71.2 (SD 7.5)% vs. 65.4 (SD 9.1)%; P < 0.05] and lower heart rate [65 (SD 9) vs. 74 (SD 9) beats/min, P < 0.001]. Additional conventional and kinematic modeling-derived indexes were highly concordant with these findings. We conclude that absence of early diastolic MAO is an easily discernible marker for relaxation-related diastolic dysfunction. Quantitation of MAO via stiffness and relaxation/viscoelasticity parameters facilitates quantitative assessment of regional (i.e., longitudinal) DF and may improve diagnosis of diastolic dysfunction.
The quantitative relationship between longitudinal and radial function in left, right, and total heart pumping in humans
Authors: Carlsson Marcus , Ugander Martin , Heiberg Einar , Arheden Hakan
Published: February 2007

The total heart volume variation (THVV) during systole has been proposed to be caused by radial function of the ventricles, but definitive data for both ventricles have not been presented. Furthermore, the right ventricle (RV) has been suggested to have a greater longitudinal pumping component than the left ventricle (LV). Therefore, we aimed to compare the stroke volume (SV) generated by radial function to the volume variation of the left, right, and total heart. To do this, we also needed to develop a new method for measuring the contribution of the longitudinal atrioventricular plane displacement (AVPD) to the RVSV (RVSVAVPD). For our study, 11 volunteers underwent cine MRI in the short- and long-axis planes and MRI flow measurement in all vessels leading to and from the heart. The left, right, and total heart showed correlations between volume variation from flow measurements and radial function calculated as SV minus the longitudinal function ( r = 0.81, P < 0.01; r = 0.80, P < 0.01; and r = 0.92, P < 0.001, respectively). Compared with the LV, the RV had a greater AVPD (23.4 ± 0.8 vs. 16.4 ± 0.5 mm), center of volume movement (13.0 ± 0.7 vs. 7.8 ± 0.4 mm), and, RVSVAVPD(82 ± 2% vs. 60 ± 2%) ( P < 0.001 for all). We found that THVV is predominantly caused by radial function of the ventricles. Longitudinal AVPD accounts for ∼80% of the RVSV, compared with ∼60% for the LVSV. This difference explains the larger portion of THVV found on the left side of the heart.
Hepatocyte growth factor and other fibroblast secretions modulate the phenotype of human bronchial epithelial cells
Authors: Myerburg Mike M. , Latoche Joseph D. , McKenna Erin E. , Stabile Laura P. , Siegfried Jill S. , Feghali-Bostwick Carol A. , Pilewski Joseph M.
Published: February 2007

The luminal airway surface is lined with epithelial cells that provide a protective barrier from the external environment and clear inhaled pathogens from the lung. To accomplish this important function, human bronchial epithelial (HBE) cells must be able to rapidly regenerate a mucociliary layer of cells following epithelial injury. Whereas epithelial-fibroblast interactions are known to modulate the airway architecture during lung development and repair, little is known about how these two cells interact. Using a primary HBE and lung fibroblast coculture system, we demonstrate that 1) subepithelial fibroblasts provide a suitable environment for differentiation of HBE cells into a polarized ciliated phenotype despite being cultured in media that induces terminal squamous differentiation and growth arrest in the absence of fibroblasts, 2) HBE cells cocultured with subepithelial fibroblasts exhibit augmented ciliogenesis, accelerated wound repair, and diminished polarized ion transport compared with cells grown in control conditions, and 3) hepatocyte growth factor (HGF) is important for subepithelial fibroblast modulation of HBE cell differentiation. These results provide a model to study fibroblast modulation of epithelial phenotype and indicate that HGF secreted by subepithelial fibroblasts contributes to HBE cell differentiation.
Hypoxia-inducible factors HIF-1α and HIF-2α are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs
Authors: Grover Theresa R. , Asikainen Tiina M. , Kinsella John P. , Abman Steven H. , White Carl W.
Published: February 2007

Respiratory distress syndrome (RDS) secondary to preterm birth and surfactant deficiency is characterized by severe hypoxemia, lung injury, and impaired production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Since hypoxia-inducible factors (HIFs) mediate the effects of both NO and VEGF in part through regulation by prolyl-hydroxylase-containing domains (PHDs) in the presence of oxygen, we hypothesized that HIF-1α and -2α in the lung are decreased following severe RDS in preterm neonatal lambs. To test this hypothesis, fetal lambs were delivered at preterm gestation (115-day gestation, term = 145 days; n = 4) and mechanically ventilated for 4 h. Lambs developed respiratory failure characterized by severe hypoxemia despite treatment with mechanical ventilation with high inspired oxygen concentrations. Lung samples were compared with nonventilated control animals at preterm (115-day gestation; n = 3) and term gestation (142-day gestation; n = 3). We found that HIF-1α protein expression decreased ( P < 0.05) and PHD-2 expression increased ( P < 0.005) at birth in normal term animals before air breathing. Compared with age-matched controls, HIF-1α protein and HIF-2α protein expression decreased by 80% and 55%, respectively ( P < 0.005 for each) in preterm lambs with RDS. Furthermore, VEGF mRNA was decreased by 40%, and PHD-2 protein expression doubled in RDS lambs. We conclude that pulmonary expression of HIF-1α, HIF-2α, and the downstream target of their regulation, VEGF mRNA, is impaired following RDS in neonatal lambs. We speculate that early disruption of HIF and VEGF expression after preterm birth and RDS may contribute to long-term abnormalities in lung growth, leading to bronchopulmonary dysplasia.
Pneumocystisstimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism
Authors: Wang Jing , Gigliotti Francis , Bhagwat Samir P. , Maggirwar Sanjay B. , Wright Terry W.
Published: February 2007

Pneumocystis carinii is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals. Recent studies have demonstrated that the host's immune response is clearly responsible for the majority of the pathophysiological changes associated with PCP. P. carinii interacts closely with alveolar epithelial cells (AECs); however, the nature and pathological consequences of the epithelial response remain poorly defined. Monocyte chemotactic protein-1 (MCP-1) is involved in lung inflammation, immunity, and epithelial repair and is upregulated during PCP. To determine whether AECs are an important source of MCP-1 in the P. carinii-infected lung, in vivo and in vitro studies were performed. In situ hybridization showed that MCP-1 mRNA was localized to cells with morphological characteristics of AECs in the lungs of infected mice. In vitro studies demonstrated that P. carinii stimulated a time- and dose-dependent MCP-1 response in primary murine type II cells that was preceded by JNK activation. Pharmacological inhibition of JNK nearly abolished P. carinii-stimulated MCP-1 production, while ERK, p38 MAPK, and TNF receptor signaling were not required. Furthermore, delivery of a JNK inhibitory peptide specifically to pulmonary epithelial cells using a recombinant adenovirus vector blocked the early lung MCP-1 response following intratracheal instillation of infectious P. carinii. JNK inhibition did not affect P. carinii-stimulated production of macrophage inflammatory protein-2 in vitro or in vivo, indicating that multiple signaling pathways are activated in P. carinii-stimulated AECs. These data demonstrate that AECs respond to P. carinii in a proinflammatory manner that may contribute to the generation of immune-mediated lung injury.
Politics and Governance: Conflicting Trends in the 1990s?
Authors: CONLAN TIMOTHY J.
Published: March 2007

The American political system has changed markedly in recent years, with important consequences for the conduct of intergovernmental relations. Historically, the noncentralized structure of political parties provided important avenues of state and local influence in Washington. Since 1974, however, dramatic changes in the parties have altered traditional relationships. Most striking has been the growth of the national party organizations, which in the last 15 years have evolved from weak and episodic entities to innovative senior partners in the party system. Nationalization has occurred as well in the interest-group arena, despite the overall expansion of public-interest-group activity. These and other developments have tended to erode state and local political influence over national policymaking. Ironically, however, such centralization stands in marked contrast to the increased innovation and assertiveness of the states in the 1980s. Reconciling these conflicting trends in politics and governance will be an important feature of intergovernmental politics in the 1990s.
Inland Waterways: Still or Turbulent Waters Ahead?
Authors: BRONZINI MICHAEL S.
Published: March 2007

Waterway transportation has played an important role in the history of the United States, and it continues to be important today. The federal government is responsible for building and maintaining the locks and channels that provide navigation, with funding coming partly from general revenues and partly from the fuel tax revenues deposited in the Inland Waterways Trust Fund. A current concern is that nearly half of the lock chambers in the system are over fifty years old, so the backlog of structures requiring major rehabilitation or replacement is large and growing. Expenditures from the trust fund at a rate sufficient to meet this need would deplete the fund in a matter of a few years. Other current policy issues include continued operation of tributary waterways with low traffic, continued subsidy of the water mode in the face of federal budget deficit reduction efforts, environmental effects of tow traffic, and disposal and beneficial reuse of dredged material.
A Sensible Public
Authors: Nincic Miroslav
Published: March 2007

The four books reviewed here share a conviction that many important influences on the international behavior of nations flow from within them, that public opinion is a significant such influence and that, as a general rule, popular preferences are sensibly related to the sound conduct of foreign policy. As such, this body of recent literature should help the discipline of international relations free itself from the hold that political realism has had on it. A conception of rationality as “reasonableness” is one of its valuable contributions; another is the insight it provides into the relationship between public opinion, governmental interests, and media views. At the same time, this article suggests ways in which the study of public opinion and foreign policy could be directed in new theoretical directions.
Creative Work
Authors: Lavery David
Published: March 2007

This article is an introduction to and systematic exposition of the key insights of cognitive psychologist Howard Gruber (Teachers College, Columbia University), whose "deeply phenomenological" case study approach, emphasizing the development of a "theory of the individual" for creative figures of great stature, has led to important discoveries about the nature-the how and not the whyof creative work.

In his explorations of the world, the individual finds out what needs doing. In his attempts to do some of it, he finds out what he can do and what he cannot. He also comes to see what he need not do. From the intersection of these possibilities there emerges a new imperative, his sense of what he must do. How "it needs" and "I can" give birth to "I must" remains enigmatic.

-Howard E. Gruber

Darwin on Man (with P. H. Barrett)

To live a creative life is one of the intentions of a creative person.

-Doris B. Wallace

Creative People at Work
Backlash in Bolivia: Regional Autonomy as a Reaction against Indigenous Mobilization
Authors: Eaton Kent
Published: February 2007

In the 1990s, Bolivia’s indigenous population mobilized to claim new political roles, and in the process, directly challenged the privileged position of economic elites within national political institutions. In response, business associations in Santa Cruz, Bolivia’s most prosperous region, began to demand regional autonomy—in contrast to the demand for authoritarianism that characterized prior generations of business elites when confronted with threatening political change. After examining Santa Cruz’ past relationship with the national government, this article explores the challenges that led economic elites in the department to seek autonomy and the strategies that they have adopted in pursuit of this goal.
The Failure of Organizational Control: Changing Party Power in the Chinese Countryside
Authors: Chen An
Published: February 2007

As frequent, violent, and organized peasant protests show, China’s reform regime has lost its once all-powerful control in the countryside. The sharp decline of village cadres’ positional authority in allocating economic resources, which began in post-Mao decollectivization, holds the key to explaining the change. Since the late 1990s, the collapse of village enterprises and the erosion of power over land have cost village cadres their remaining economic levers to engage the villagers as well as their incentives to work for the party-state. The loss of the regime’s grip on village cadres and the loss of command by village cadres on peasants have almost synchronized, causing the traditional structure of organizational control to crumble in vast rural areas. In the new, prevailing patterns of village governance, party power is becoming increasingly irrelevant.
But Is It for Real? The British Columbia Citizens’ Assembly as a Model of State-Sponsored Citizen Empowerment
Authors: Lang Amy
Published: February 2007

Emerging forms of empowered participatory governance have generated considerable scholarly excitement, but critics continue to ask if such initiatives are “for real”: Are participatory governance processes sufficiently independent? Do citizen participants make good policy choices? An in-depth look at the case of the British Columbia Citizens’ Assembly on Electoral Reform suggests that real citizen empowerment depends on both the institutional constraints of the participa-tory setting and how citizen interests and arguments for policy outcomes crystallize over the course of a participatory process.