bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Akt Signaling in Vascular Homeostasis and Angiogenesis
Authors: Shiojima Ichiro , Walsh Kenneth
Published: July 2002

Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase–dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
Phosphatidylinositol 3-Kinase Functionally Compartmentalizes the Concurrent G
s
Signaling During β
2
-Adrenergic Stimulation
Authors: Jo Su-Hyun , Leblais Veronique , Wang Ping H. , Crow Michael T. , Xiao Rui-Ping
Published: July 2002

Compartmentation of intracellular signaling pathways serves as an important mechanism conferring the specificity of G protein-coupled receptor (GPCR) signaling. In the heart, stimulation of β
2
-adrenoceptor (β
2
-AR), a prototypical GPCR, activates a tightly localized protein kinase A (PKA) signaling, which regulates substrates at cell surface membranes, bypassing cytosolic target proteins (eg, phospholamban). Although a concurrent activation of β
2
-AR-coupled G
i
proteins has been implicated in the functional compartmentation of PKA signaling, the exact mechanism underlying the restriction of the β
2
-AR-PKA pathway remains unclear. In the present study, we demonstrate that phosphatidylinositol 3-kinase (PI3K) plays an essential role in confining the β
2
-AR-PKA signaling. Inhibition of PI3K with LY294002 or wortmannin enables β
2
-AR-PKA signaling to reach intracellular substrates, as manifested by a robust increase in phosphorylation of phospholamban, and markedly enhances the receptor-mediated positive contractile and relaxant responses in cardiac myocytes. These potentiating effects of PI3K inhibitors are not accompanied by an increase in β
2
-AR-induced cAMP formation. Blocking G
i
or Gβγ signaling with pertussis toxin or βARK-ct, a peptide inhibitor of Gβγ, completely prevents the potentiating effects induced by PI3K inhibition, indicating that the pathway responsible for the functional compartmentation of β
2
-AR-PKA signaling sequentially involves G
i
, Gβγ, and PI3K. Thus, PI3K constitutes a key downstream event of β
2
-AR-G
i
signaling, which confines and negates the concurrent β
2
-AR/G
s
-mediated PKA signaling.
Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing
Authors: Michelakis Evangelos D. , Hampl Vaclav , Nsair Ali , Wu XiCheng , Harry Gwyneth , Haromy Al , Gurtu Rachita , Archer Stephen L.
Published: July 2002

Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O
2
tension is detected by an unidentified redox sensor, which controls K
+
channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O
2
sensors. Mitochondria-derived activated oxygen species (AOS), like H
2
O
2
, can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K
+
channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K
+
current and constrict PAs while increasing AOS production and outward K
+
current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H
2
O
2
production. Similarly, production of AOS and H
2
O
2
is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H
2
O
2
, can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.
Apolipoprotein E Mediates the Retention of High-Density Lipoproteins by Mouse Carotid Arteries and Cultured Arterial Smooth Muscle Cell Extracellular Matrices
Authors: Olin-Lewis Katherine , Benton Jeana L. , Rutledge John C. , Baskin Denis G. , Wight Thomas N. , Chait Alan
Published: July 2002

Lipoprotein retention in the vascular extracellular matrix (ECM) plays a critical role in atherogenesis. Previous studies demonstrated the presence of apo A-I and E in atherosclerotic lesions, suggesting that HDL may be trapped by the artery wall. We sought to determine mechanisms by which HDL could be bound and retained by the arterial wall, and whether apo E was a principal determinant of this binding. We evaluated in situ accumulation of fluorescently labeled DiI-human HDL±apo E in perfused carotid arteries from apo E–null mice. Apo E was important in mediating HDL binding to the vascular wall, with a 48±16% increase in accumulation of DiI-labeled apo E–containing HDL (HDL
3
+E) compared with DiI-apo E–free HDL (HDL
3
−E) (
P
=0.003). To investigate possible mechanisms responsible for retention, we assessed binding of unlabeled HDL
3
−E and HDL
3
+E to ECM generated by cultured arterial smooth muscle cells. Similar to the in situ carotid artery data, HDL
3
+E bound better to the ECM than did HDL
3
−E (3-fold lower K
a
and 3.5-fold higher B
max
for HDL
3
+E versus HDL
3
−E). These differences were eliminated after either neutralization of arginine residues on apo E or digestion of matrix with chondroitin ABC lyase, suggesting that chondroitin and/or dermatan sulfate proteoglycans were responsible for apo E–mediated increased binding. These findings demonstrate that HDL can bind to both intact murine carotid arteries and smooth muscle cell–derived ECM, and that apo E is a principal determinant in mediating the ability of HDL to be trapped and retained via its interaction with ECM proteoglycans.
Induction of Bone-Type Alkaline Phosphatase in Human Vascular Smooth Muscle Cells
Authors: Shioi Atsushi , Katagi Miwako , Okuno Yasuhisa , Mori Katsuhito , Jono Shuichi , Koyama Hidenori , Nishizawa Yoshiki
Published: July 2002

Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-γ (IFN-γ) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1α,25-dihydroxyvitamin D
3
(1,25(OH)
2
D
3
) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-γ and 1,25(OH)
2
D
3
. To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-γ and 1,25(OH)
2
D
3
. THP-1 cells or PBMCs induced ALP activity and its gene expression in HVSMCs and the cells with high expression of ALP calcified their extracellular matrix by the addition of β-glycerophosphate. Thermostability and immunoassay showed that ALP induced in HVSMCs was bone-specific enzyme. We further identified tumor necrosis factor-α (TNF-α) and oncostatin M (OSM) as major factors inducing ALP in HVSMCs in the culture supernatants of THP-1 cells. TNF-α and OSM, only when applied together, increased ALP activities and in vitro calcification in HVSMCs in the presence of IFN-γ and 1,25(OH)
2
D
3
. These results suggest that macrophages may contribute to the development of vascular calcification through producing various inflammatory mediators, especially TNF-α and OSM.
Long-Term Disability After First-Ever Stroke and Related Prognostic Factors in the Perth Community Stroke Study, 1989–1990
Authors: Hankey Graeme J. , Jamrozik Konrad , Broadhurst Robyn J. , Forbes Susanne , Anderson Craig S.
Published: July 2002

Background and Purpose

—

Few reliable estimates of the long-term functional outcome after stroke are available. This population-based study aimed to describe disability, dependency, and related independent prognostic factors at 5 years after a first-ever stroke in patients in Perth, Western Australia.

Methods

—

All individuals with a suspected acute stroke who were resident in a geographically defined region (population, 138 708) of Perth, Western Australia, were registered prospectively and assessed according to standardized diagnostic criteria over a period of 18 months in 1989 to 1990. Patients were followed up prospectively at 4 and 12 months and 5 years after the index event.

Results

—

There were 370 cases of first-ever stroke, and 277 patients survived to 30 days. Of these early survivors, 152 (55%) were alive at 5 years, and among those who were neither institutionalized (n=146) nor disabled (n=129) at the time of their stroke, 21 (14%) were institutionalized in a nursing home, and 47 (36%) were disabled. The most important predictors of death or disability at 5 years were increasing age, baseline disability defined by a Barthel Index score of <20/20 (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.7 to 14), moderate hemiparesis (OR, 2.7; 95% CI, 1.1 to 6.2), severe hemiparesis (OR, 4.5; 95% CI, 1.1 to 19), and recurrent stroke (OR, 9.4; 95% CI, 3.0 to 30). A low level of activity before the stroke was a significant predictor of institutionalization, and subsequent recurrent stroke was a consistent, independent predictor of institutionalization, disability, and death or institutionalization, increasing the odds of each of these 3 adverse outcomes by 5- to 15-fold.

Conclusions

—

Among 30-day survivors of first-ever stroke, about half survive 5 years; of survivors, one third remain disabled, and 1 in 7 are in permanent institutional care. The major modifiable predictors of poor long-term outcome are a low level of activity before the stroke and subsequent recurrent stroke. Efforts to increase physical activity among the elderly and to prevent recurrent stroke in survivors of a first stroke are likely to reduce the long-term burden of cerebrovascular disease.
Dissecting Aneurysms of Intracranial Carotid Circulation
Authors: Ohkuma Hiroki , Suzuki Shigeharu , Ogane Kazumi
Published: July 2002

Background and Purpose

—

Clinical features of nontraumatic dissecting aneurysms of intracranial carotid circulation remain unclear because investigation of this disease has been limited to case reports. The aim of this study was to investigate the clinical features of this disease through the use of cooperatively collected cases.

Methods

—

The cases diagnosed as dissecting aneurysms of intracranial carotid circulation on the basis of clinical signs and neuroradiological findings in 46 stroke centers from 1995 through 1999 were collected, and their clinical features were analyzed.

Results

—

Forty-nine cases of dissecting aneurysms of intracranial carotid circulation were collected. Thirty-two patients presented with subarachnoid hemorrhage (SAH), and 17 presented with cerebral ischemia. The ratio of this disease to all intracranial dissecting aneurysms treated in the same institutes for the same period was 19.1%, and the ratio of SAH resulting from this disease to SAH of unverified origin treated in the same institutes for the same period was 6.2%. The predominant site of lesion was the internal carotid artery in 18 of 32 patients (56%) with SAH and the anterior cerebral artery in 13 of 17 patients (76%) with cerebral ischemia. The predominant angiographic findings were that stenosis with dilatation occurred in 20 of 32 patients (63%) with SAH and stenosis without dilatation was seen in 11 of 17 patients (65%) with cerebral ischemia. Poor prognosis was seen in 21 of 32 patients (66%) with SAH, which was due largely to rebleeding seen preoperatively, during operation, and even postoperatively when clipping or wrapping of the aneurysmal bulge was performed.

Conclusions

—

Nontraumatic dissecting aneurysm of intracranial carotid circulation is not as rare as expected. It seems to be one of the important causes of SAH of unverified origin.
Hemodynamic Studies in Early Ischemic Stroke
Authors: Akopov S. , Whitman G.T.
Published: July 2002

Background and Purpose

—

After acute stroke, it is often standard practice to obtain magnetic resonance angiography (MRA) to seek evidence of a plausible stroke mechanism. However, hemodynamic patterns after acute ischemic stroke are variable and dynamic. We evaluated information obtained by serial transcranial Doppler ultrasonography (TCD) examinations within the first week after acute ischemic stroke and compared it with that obtained from a single MRA study.

Methods

—

Forty-seven patients (aged 61±7 years) with acute ischemic hemispheric stroke were examined. TCD was performed within 24 hours, from 24 to 48 hours, and 4 to 8 days after ictus. Norms for TCD examination were determined in an age-matched control group that included 41 subjects without cerebrovascular disease (aged 57±10 years).

Results

—

In 17 stroke patients, the results of initial TCD examination were normal, although TCD follow-up showed gradual deterioration of middle cerebral artery (MCA) for 1 patient with normal MRA. In 12 patients, initial TCD study and MRA showed MCA or posterior cerebral artery occlusion. Serial TCD examinations documented recanalization (6 patients), formation of a residual MCA stenosis (1 patient), or progressive deterioration of flow through a symptomatic MCA (1 patient), not evident on MRA. In 5 patients MRA was normal, but early TCD demonstrated signs of previous recanalization (transitory hyperemia, slow flow restoration). In 2 patients with MCA branch occlusion, MRA suggested occlusion but failed to document either improvement (1 patient) or deterioration (1 patient) of flow that was evident with serial TCD. In 4 patients with proximal MCA stenosis and 5 patients with internal carotid artery occlusion or stenosis, serial TCD demonstrated different patterns of collateralization and suggested dynamic collateralization patterns after stroke that were not evident on MRA.

Conclusions

—

Serial TCD examination may reveal dynamic changes in cerebral circulation that may be missed on a single MRA study.
Can Transcranial Ultrasonication Increase Recanalization Flow With Tissue Plasminogen Activator?
Authors: Ishibashi Toshihiro , Akiyama Masahiko , Onoue Hisashi , Abe Toshiaki , Furuhata Hiroshi
Published: July 2002

Background and Purpose

—

In thrombolytic therapy for acute ischemic stroke, it is essential to obtain rapid thrombolysis before ischemic neuronal injury occurs. To develop a new technique of thrombolysis for acute ischemic stroke, the effect of transcranially applied ultrasound (TUS) on thrombolysis was examined.

Methods

—

An occlusion model of rabbit femoral artery was produced with thrombin after establishment of stenotic flow and endothelial damage. After stable occlusion was confirmed, monteplase (mtPA) was administered intravenously, and ultrasound (490 kHz, 0.13 W/cm
2
) was applied through a piece of temporal bone (TUS group; n=9). The control group received mtPA alone (tissue plasminogen activator [tPA] group; n=12). To verify the efficacy of TUS, femoral artery flow was measured during the procedure.

Results

—

The recanalization ratio was 16.7% (2 of 12) in the tPA group and 66.7% (6 of 9) in the TUS group. The recanalization ratio in the TUS group was higher than that in the tPA group (
P
=0.03). Patency flow ratio, which was defined as recanalization flow divided by baseline flow, of the TUS group (44.6±13.9%) was significantly greater than that of the tPA group (9.9±6.8%) at 60 minutes (
P
=0.025). Patency flow ratio became higher in the TUS group than in the tPA group between 20 and 30 minutes from the start of thrombolysis.

Conclusions

—

Low-frequency and low-intensity TUS enhanced thrombolysis by mtPA in a rabbit femoral artery occlusion model. This technique should be clinically useful for thrombolysis in acute ischemic stroke.
Acute Basilar Artery Occlusion Treated With Combined Intravenous Abciximab and Intra-arterial Tissue Plasminogen Activator
Authors: Eckert Bernd , Koch Christoph , Thomalla Götz , Roether Joachim , Zeumer Herrmann
Published: July 2002

Background

—

Acute vertebrobasilar occlusion remains a disease with a high mortality even after treatment by local intra-arterial fibrinolysis. Adjunctive treatment with platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab may facilitate recanalization and improve the neurological outcome. Results after treatment of 3 patients by combined intravenous abciximab and local intra-arterial tissue plasminogen activator (tPA) are reported.

Case Descriptions

—

Treatment was performed within 6 hours of stroke onset. Angiography revealed embolic occlusion of the basilar artery in 2 patients and atherothrombotic occlusion at the vertebrobasilar junction in 1 patient. Therapy consisted of intravenous abciximab bolus administration (0.25 mg/kg) followed by 12-hour infusion therapy (0.125 μg/kg per minute) and local intra-arterial thrombolysis with tPA (10 mg/h). Heparin was only applied for catheter flushing (500 IU/h). The patient with the atherothrombotic occlusion was treated with additional percutaneous transluminal angioplasty and stenting. Complete recanalization of the basilar artery occurred in 2 patients, whose conditions improved clinically to functional independence. In the third patient only partial recanalization was seen, with only slight clinical improvement. This patient died of cardiac failure 2 months later. Besides a subtle subarachnoid hemorrhage (n=1), no intracranial or extracranial bleeding complication was observed.

Conclusions

—

The combination of glycoprotein IIb/IIIa receptor inhibitor with local intra-arterial tPA might be a promising therapy for patients with acute vertebrobasilar occlusion. Further studies are necessary to define the clinical benefit and the bleeding rate of this new pharmacological approach.
Correlation of Apparent Diffusion Coefficient and Computed Tomography Density in Acute Ischemic Stroke
Authors: Kucinski Thomas , Väterlein Ole , Glauche Volkmar , Fiehler Jens , Klotz Ernst , Eckert Bernd , Koch Christoph , Röther Joachim , Zeumer Hermann
Published: July 2002

Background and Purpose

—

Diffusion-weighted MR imaging is very sensitive for the detection of restricted molecular water diffusion in acute ischemic stroke. CT is sensitive to net water uptake in ischemic edema. We compared the decrease in the apparent diffusion coefficient (ADC) in diffusion-weighted MR imaging with CT density changes to study the correlation between diffusion restriction and water uptake in acute stroke patients.

Methods

—

Twenty-five patients with acute ischemic stroke of the anterior cerebral circulation underwent MR and CT imaging 1.3 to 5.4 hours after symptom onset. ADC and CT data were transferred into a common 3-dimensional space, and regions of decreased ADC (dADC) were superimposed onto the corresponding CT. Mean values of ADC and Hounsfield units (HU) were determined in comparison with the nonaffected hemisphere.

Results

—

Mean decrease in ADC (dADC) was 170±53× 10
−6
mm
2
/s and corresponded to a decrease (dCT) in CT density of 1.3±0.7 HU. dCT showed a continuous linear decrease of 0.4 HU/h (
r
=0.55,
P
<0.01), whereas the decrease is ADC was almost complete after 1.5 hours. A correlation between the decrease in ADC and dCT was found (
r
=0.41,
P
=0.04).

Conclusions

—

The severity of diffusion restriction correlates with net water uptake in acute ischemic stroke. However, the underlying pathophysiology and different time courses indicate a common reason rather than a direct causality for both phenomena. The time delay and low value of CT density changes provide a reasonable explanation for the higher sensitivity of MR imaging in ischemic stroke.
Use of an Inspiratory Impedance Valve Improves Neurologically Intact Survival in a Porcine Model of Ventricular Fibrillation
Authors: Lurie Keith G. , Zielinski Todd , McKnite Scott , Aufderheide Tom , Voelckel Wolfgang
Published: July 2002

Background
—

This study evaluated the potential for an inspiratory impedance threshold valve (ITV) to improve 24-hour survival and neurological function in a pig model of cardiac arrest.

Methods and Results
—

Using a randomized, prospective, and blinded design, we compared the effects of a sham versus active ITV on 24-hour survival and neurological function. After 6 minutes of ventricular fibrillation (VF), followed by 6 minutes of cardiopulmonary resuscitation (CPR) with either a sham or an active valve, anesthetized pigs received 3 sequential 200-J shocks. If VF persisted, they received epinephrine (0.045 mg/kg), 90 seconds of CPR, and 3 more 200-J shocks. A total of 11 of 20 pigs (55%) in the sham versus 17 of 20 (85%) in the active valve group survived for 24 hours (
P
<0.05). Neurological scores were significantly higher with the active valve; the cerebral performance score (1=normal, 5=brain death) was 2.2±0.2 with the sham ITV versus 1.4±0.2 with the active valve (
P
<0.05). A total of 1 of 11 in the sham versus 12 of 17 in the active valve group had completely normal neurological function (
P
<0.05). Peak end-tidal CO
2
(P
etco
2
) values were significantly higher with the active valve (20.4±1.0) than the sham (16.8±1.5) (
P
<0.05). P
etco
2
>18 mm Hg correlated with increased survival (
P
<0.05).

Conclusions
—

Use of a functional ITV during standard CPR significantly improved 24-hour survival rates and neurological recovery. P
etco
2
and systolic blood pressure were also significantly higher in the active valve group. These data support further evaluation of ITV during standard CPR.
Adrenomedullin, an Endogenous Peptide, Counteracts Cardiovascular Damage
Authors: Shimosawa Tatsuo , Shibagaki Yugo , Ishibashi Kotaro , Kitamura Kazuo , Kangawa Kenji , Kato Shigeaki , Ando Katsuyuki , Fujita Toshiro
Published: July 2002

Background
—

Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of pro-adrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo.

Methods and Results
—

Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM
−/−
mutation in mice was embryonic lethal without any apparent phenotypic changes, AM
+/−
mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM
+/+
mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt–treated AM
+/−
mice, without the AM upregulation that was observed in Ang II/salt–treated AM
+/+
mice. In AM
+/−
mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt–treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading.

Conclusions
—

The evidence presented supports the hypothesis that endogenous AM possesses a protective action against cardiovascular damage, possibly through the inhibition of oxidative stress production.
Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart
Authors: Toma Catalin , Pittenger Mark F. , Cahill Kevin S. , Byrne Barry J. , Kessler Paul D.
Published: July 2002

Background
—

Cellular cardiomyoplasty has been proposed as an alternative strategy for augmenting the function of diseased myocardium. We investigated the potential of human mesenchymal stem cells (hMSCs) from adult bone marrow to undergo myogenic differentiation once transplanted into the adult murine myocardium.

Methods and Results
—

A small bone marrow aspirate was taken from the iliac crest of healthy human volunteers, and hMSCs were isolated as previously described. The stem cells, labeled with
lacZ
, were injected into the left ventricle of CB17 SCID/
beige
adult mice. At 4 days after injection, none of the engrafted hMSCs expressed myogenic markers. A limited number of cells survived past 1 week and over time morphologically resembled the surrounding host cardiomyocytes. Immunohistochemistry revealed de novo expression of desmin, β-myosin heavy chain, α-actinin, cardiac troponin T, and phospholamban at levels comparable to those of the host cardiomyocytes; sarcomeric organization of the contractile proteins was observed. In comparison, neither cardiac troponin T nor phospholamban was detected in the myotubes formed in vitro by MyoD-transduced hMSCs.

Conclusions
—

The purified hMSCs from adult bone marrow engrafted in the myocardium appeared to differentiate into cardiomyocytes. The persistence of the engrafted hMSCs and their in situ differentiation in the heart may represent the basis for using these adult stem cells for cellular cardiomyoplasty.
Coronary Collateral Size, Flow Capacity, and Growth
Authors: Rockstroh Julia , Brown B. Greg
Published: July 2002

Background
—

Stimulation of coronary collateral growth has potential clinical value, yet techniques to assess such growth in patients are limited.

Methods and Results
—

A cineangiographic approach to classify the dominant collaterals and to quantify their lumen caliber and flow capacity was developed and validated. For measurement of 0.4- to 1.5-mm-diameter phantoms, mean error ranged from −0.01 to +0.02 mm. To illustrate the utility of such a method, 52 collateral pathways were measured in 13 patients with 17 occluded arteries before and after 10 years of intensive lipid therapy. The mean variance, ς, of 9 separate measurements of each collateral was ±0.101 mm. At pretreatment, collateral diameter averaged 0.50±0.11 mm (SD) (range, 0.3 to 1.4 mm) without tapering or central narrowing. Over 10 years, mean increase in diameter was +16% (
P
=0.028); in area, +64% (
P
=0.015); and in estimated flow capacity, +214% (
P
=0.009). Certain lipoprotein characteristics tended to predict collateral growth. Patients for whom angina disappeared during 10 years had a greater increase in flow capacity than those for whom it persisted (+331% versus 4%;
P
=0.05).

Conclusions
—

Coronary collateral diameter can be estimated with a precision of 0.10 mm. Flow capacity of the network is well approximated by measurement of the 2 or 3 largest connections serving an occluded artery. Initial studies with this method show that disappearance of angina is significantly associated with growth in collateral flow capacity. Collateral growth tends to associate with lipid therapy and with certain in-treatment lipid measures.
Targeting Kinin B
1
Receptor for Therapeutic Neovascularization
Authors: Emanueli Costanza , Bonaria Salis Maria , Stacca Tiziana , Pintus Gianfranco , Kirchmair Rudolf , Isner Jeffrey M. , Pinna Alessandra , Gaspa Leonardo , Regoli Domenico , Cayla Cecile , Pesquero João B. , Bader Michael , Madeddu Paolo
Published: July 2002

Background

—

Kinins are modulators of cardiovascular function. After ischemic injury, enhanced kinin generation may contribute in processes responsible for tissue healing.

Methods and Results

—

Using pharmacological and genetic approaches, we investigated the role of kinin B
1
receptor in reparative angiogenesis in a murine model of limb ischemia. The effect of B
1
pharmacological manipulation on human endothelial cell proliferation and apoptosis was also studied in vitro. Abrogation of B
1
signaling dramatically inhibited the native angiogenic response to ischemia, severely compromising blood perfusion recovery. Outcome was especially impaired in B
1
knockouts that showed a very high incidence of limb necrosis, eventually leading to spontaneous auto-amputation. Conversely, local delivery of a long-acting B
1
receptor agonist enhanced collateral vascular growth in ischemic skeletal muscle, accelerated the rate of perfusion recovery, and improved limb salvage. In vitro, B
1
activation stimulated endothelial cell proliferation and survival, whereas B
1
antagonism induced apoptosis.

Conclusions

—

Our results indicate that the B
1
plays an essential role in the host defense response to ischemic injury. B
1
signaling potentiation might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.
Bone Marrow–Derived Regenerated Cardiomyocytes (CMG Cells) Express Functional Adrenergic and Muscarinic Receptors
Authors: Hakuno Daihiko , Fukuda Keiichi , Makino Shinji , Konishi Fusako , Tomita Yuichi , Manabe Tomohiro , Suzuki Yusuke , Umezawa Akihiro , Ogawa Satoshi
Published: July 2002

Background

—

We recently reported that cardiomyocytes could be differentiated from bone marrow mesenchymal stem cells in vitro by 5-azacytidine treatment. In native cardiomyocytes, adrenergic and muscarinic receptors play crucial roles in mediating heart rate, conduction velocity, contractility, and cardiac hypertrophy. We investigated whether these receptors are expressed in differentiated CMG cells, and if so, whether they have downstream signaling systems.

Methods and Results

—

Reverse transcription–polymerase chain reaction revealed that CMG cells had already expressed α
1A
-, α
1B
-, and α
1D
-adrenergic receptor mRNA before 5-azacytidine treatment, whereas expression of β
1
-, β
2
-adrenergic and M
1
-, M
2
-muscarinic receptors was first detected at 1 day. Phenylephrine dose-dependently induced phosphorylation of ERK1/2, which was completely inhibited by prazosin, and significantly increased cell size. Isoproterenol augmented cAMP by 38-fold, which was fully inhibited by propranolol. Isoproterenol (10
−7
mol/L) increased the spontaneous beating rate by 47.6% (basal, 127±16 bpm), and propranolol and CGP20712A (β
1
-selective blocker) reduced it by 79.0% and 71.0%, respectively, whereas ICI118551 (β
2
-selective blocker) induced slight reduction. Cell motion, percent shortening, and contractile velocity were increased by 37.5%, 26.9%, and 50.6%, respectively, in response to isoproterenol. Phenylephrine and isoproterenol augmented ANP and BNP gene expressions. Carbachol increased IP
3
by 32-fold, which was markedly inhibited by atropine as well as AFDX116 (M
2
-selective blocker) measured by radioimmunoassay.

Conclusions

—

These findings indicate that CMG cells expressed α
1A
, α
1B
, and α
1D
receptors before differentiation and expressed β
1
, β
2
, M
1
, and M
2
receptors after they obtained the cardiomyocyte phenotype. These receptors had functional signal transduction pathways and could modulate cell function.
Antioxidative Properties of Acetylsalicylic Acid on Vascular Tissues From Normotensive and Spontaneously Hypertensive Rats
Authors: Wu Rong , Lamontagne Daniel , de Champlain Jacques
Published: July 2002

Background

—

The mechanisms of the beneficial cardiovascular effects of acetylsalicylic acid (ASA, aspirin) therapy are not completely understood. Oxidative stress and inflammation play important roles in the development of cardiovascular diseases.

Methods and Results

—

In this study, we tested the hypothesis that ASA treatment could reduce superoxide anion (O
2
−
) generation in aortic ring and in cultured aortic smooth muscle cells (SMCs) from normotensive (WKY) and hypertensive (SHRs) rats by means of the Lucigenin-enhanced chemiluminescence method. Although ASA did not show any short-term effect in vitro and in vivo, long-term oral treatment (100 mg/kg/day, 12 days) significantly reduced the basal O
2
−
production by 27% and 45% in aorta of normotensive and hypertensive rats, respectively, in association with a reduction of the NAD(P)H oxidase activity in both groups. These effects were dose-dependent from 10 to 100 mg/kg/day. Similar effects were observed in SMCs following long-term incubation (48 hours) with ASA. ASA treatment also completely inhibited the angiotensin II–induced hypertension and O
2
−
production. Moreover, ASA treatment significantly improved the impaired aortic relaxation response to acetylcholine and markedly attenuated the age-dependent development of hypertension in SHRs.

Conclusion

—

Long-term ASA treatment in vivo markedly reduced vascular O
2
−
production through lowering the NAD(P)H oxidase activity in both normotensive and hypertensive rats. These antioxidative properties of ASA are likely involved in the restoration of aortic vasorelaxation, in the attenuation of the development of hypertension in young SHRs, and in the prevention of hypertension following long-term angiotensin II infusion.
Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy
Authors: Hirotani Shinichi , Otsu Kinya , Nishida Kazuhiko , Higuchi Yoshiharu , Morita Takashi , Nakayama Hiroyuki , Yamaguchi Osamu , Mano Toshiaki , Matsumura Yasushi , Ueno Hikaru , Tada Michihiko , Hori Masatsugu
Published: July 2002

Background
—

Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-κB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein–coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.

Methods and Results
—

Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-κB activation. Antioxidants such as
N
-acetyl cysteine,
N
-mercaptopropionyl glycine, and vitamin E attenuated the NF-κB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IκBα led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist–induced NF-κB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-κB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-κB activation.

Conclusions
—

These data indicate that GPCR agonist–induced cardiac hypertrophy is mediated through NF-κB activation via the generation of ROS. ASK1 is involved in GPCR agonist–induced NF-κB activation and resulting hypertrophy.
Ubiquitin-Proteasome Pathway as a New Target for the Prevention of Restenosis
Authors: Meiners Silke , Laule Michael , Rother Wim , Guenther Christoph , Prauka Ines , Muschick Peter , Baumann Gert , Kloetzel Peter-Michael , Stangl Karl
Published: July 2002

Background
—

The ubiquitin-proteasome system is the major intracellular protein degradation pathway in eucaryotic cells. It regulates central mediators of proliferation, inflammation, and apoptosis that are fundamental pathomechanisms in the development of vascular restenosis.

Methods and Results
—

Effects of proteasome inhibition on neointima formation were studied in a balloon injury model in the rat carotid artery. Local application of the proteasome inhibitor MG132 (1 mmol/L) resulted in significant inhibition of intimal hyperplasia, that is, by 74% (
P
=0.008). This effect was accompanied by decreased proliferation, reduced infiltration of macrophages, and prolonged apoptosis, as determined by immunohistochemical and TUNEL analyses. Functional effects of proteasome inhibition on proliferation, activation of nuclear factor kappa B, and apoptosis were further characterized in rat primary vascular smooth muscle cells. MG132 dose-dependently inhibited vascular smooth muscle cell proliferation with 50% inhibition at 10 μmol/L. TNFα-induced degradation of IκBα and β was blocked, and activation of nuclear factor kappa B was suppressed in a concentration-dependent manner in bandshift assays. Moreover, proteasome inhibition (1 to 50 μmol/L MG132) induced apoptotic cell death up to 80%, as confirmed by DNA/Histone-ELISA and TUNEL-FACS analysis. Specificity of proteasome inhibition was shown by accumulation of multiubiquitinylated proteins and accumulation of specific proteasomal substrates.

Conclusions
—

These proof-of-principle experiments demonstrate that inhibition of the ubiquitin-proteasome system effectively reduces neointima formation in vivo, which corresponds to strong antiproliferative, anti-inflammatory, and proapoptotic effects in vitro and in vivo. Our data suggest the ubiquitin-proteasome system as a new target in the prevention of vascular restenosis.
Weight Loss Reduces C-Reactive Protein Levels in Obese Postmenopausal Women
Authors: Tchernof André , Nolan Amy , Sites Cynthia K. , Ades Philip A. , Poehlman Eric T.
Published: July 2002

Background

—

C-reactive protein (CRP) has been proposed as an independent risk factor for cardiovascular disease and has been positively associated with body weight and body fatness. We examined the hypothesis that weight loss would reduce plasma CRP levels in obese postmenopausal women.

Methods and Results

—

In a sample of 61 obese (body mass index, 35.6±5.0 kg/m
2
), postmenopausal women (age, 56.4±5.2 years), we found that plasma CRP levels were positively associated with dual x-ray absorptiometry–measured total body fatness (
r
=0.36,
P
<0.005) and CT-measured intra-abdominal body fat area (
r
=0.30,
P
<0.02). Significant correlations were also found between plasma CRP and triglyceride levels (
r
=0.33,
P
<0.009) and glucose disposal measured by the hyperinsulinemic-euglycemic clamp technique (
r
=−0.29,
P
<0.03). Twenty-five of the 61 women tested at baseline completed a weight loss protocol. The average weight loss was 14.5±6.2 kg (−15.6%,
P
<0.0001), with losses of 10.4±5.4 kg fat mass (−25.0%,
P
<0.0001) and 2.8±1.4 kg fat-free mass (−6.0%,
P
<0.0001). Visceral and subcutaneous fat areas were reduced by −36.4% and −23.7%, respectively (
P
<0.0001). Plasma CRP levels were significantly reduced by weight loss: average −32.3%, from 3.06 (+0.69, −1.29) to 1.63 (+0.70, −0.75) μg/mL (
P
<0.0001, medians and interquartile differences). Changes in body weight and in total body fat mass were both positively associated with plasma CRP level reductions.

Conclusions

—

Adiposity was a significant predictor of plasma CRP in postmenopausal women on a cross-sectional basis. Moreover, caloric restriction–induced weight loss decreased plasma CRP levels. Weight loss may represent an important intervention to reduce CRP levels, which may mediate part of its cardioprotective effects in obese postmenopausal women.
Rotational Atherectomy Does Not Reduce Recurrent In-Stent Restenosis
Authors: vom Dahl Juergen , Dietz Ulrich , Haager Philipp K. , Silber Sigmund , Niccoli Luigi , Buettner Hans Juergen , Schiele Francois , Thomas Martyn , Commeau Philippe , Ramsdale David R. , Garcia Eulogio , Hamm Christian W. , Hoffmann Rainer , Reineke Thorsten , Klues Heinrich G.
Published: July 2002

Background

—

Aim of this trial was to compare rotational atherectomy followed by balloon angioplasty (rotablation [ROTA] group) with balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA] group) alone in patients with diffuse in-stent restenosis.

Methods and Results

—

The ARTIST study is a multicenter, randomized, prospective European trial with 298 patients with in-stent restenosis>70% (mean lesion length, 14±8 mm) in stents, implanted in coronary arteries for ≥3 months. In the PTCA group, angioplasty was performed at the discretion of the local investigator, and rotablation was performed by using a stepped-burr approach followed by adjunctive PTCA with low (≤6 atm) inflation pressure. Intravascular ultrasound during the intervention and at follow-up was used in a substudy in 86 patients (45 PTCA, 41 ROTA). Angiography demonstrated no difference regarding the short-term outcome, with equivalent procedural success rates defined as remaining stenosis <30% (89% PTCA, 88% ROTA). However, the results showed that, in the long term, PTCA was a significantly better strategy than ROTA. Mean net gain in minimal lumen diameter was 0.67 mm and 0.45 mm for PTCA and ROTA, respectively (
P
=0.0019). Mean gain in diameter stenosis was 25% and 17% (
P
=0.002), resulting in restenosis (≥50%) rates of 51% (PTCA) and 65% (ROTA) (
P
=0.039). By intravascular ultrasound, the major difference was the missing stent over-expansion during PTCA after ROTA. Six-month event-free survival was significantly higher after PTCA (91.3%) compared with ROTA (79.6%,
P
=0.0052).

Conclusions

—

In terms of the primary objective of the study, PTCA produced a significantly better long-term outcome than ROTA followed by adjunctive low-pressure PTCA.
Magnetic Resonance–Guided Coronary Artery Stent Placement in a Swine Model
Authors: Spuentrup Elmar , Ruebben Alexander , Schaeffter Tobias , Manning Warren J. , Günther Rolf W. , Buecker Arno
Published: July 2002

Background
—

Magnetic resonance (MR)–guided coronary artery stent placement is a challenging vascular intervention because of the small size of the coronary arteries combined with incessant motion during the respiratory and cardiac cycles. These obstacles necessitate higher temporal and higher spatial resolution real-time MR imaging techniques when compared with interventional peripheral MR angiography.

Methods and Results
—

A new, ultrafast, real-time MR imaging technique that combines steady-state free precession (SSFP) for high signal-to-noise ratio and radial k-space sampling (rSSFP) for motion artifact suppression was implemented on a 1.5-T clinical whole-body interventional MR scanner. The sliding window reconstruction technique yielded a frame rate of 15/s allowing for data acquisition during free breathing and without cardiac triggering. Eleven balloon-expandable stainless steel coronary stents were placed in both coronary arteries of 7 pigs (40 to 70 kg body weight) using a nitinol guidewire and passive device visualization. Position of the coronary stents was controlled by a navigator-gated free-breathing ECG–triggered three-dimensional SSFP coronary MRA sequence and confirmed visually on the ex vivo heart. The presented real-time MR imaging sequence reliably allowed for high-quality coronary MR fluoroscopy without motion artifacts in all pigs. Ten of 11 coronary stents were correctly placed under MR guidance. One stent dislodged proximally from the left main coronary artery because of too-small balloon size. Stent dislocation was correctly predicted during real-time MR imaging.

Conclusion
—

The presented approach allows for real-time MR-guided coronary artery stent placement in a swine model.
Advanced Glycation End Products Activate Endothelium Through Signal-Transduction Receptor RAGE
Authors: Basta Giuseppina , Lazzerini Guido , Massaro Marika , Simoncini Tommaso , Tanganelli Piero , Fu Caifeng , Kislinger Thomas , Stern David M. , Schmidt Ann Marie , De Caterina Raffaele
Published: July 2002

Background
—

The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation.

Methods and Results
—

AGEs, RAGE, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin are expressed in an overlapping manner in human inflamed rheumatoid synovia, especially within the endothelium. In primary cultures of human saphenous vein endothelial cells, engagement of RAGE by heterogeneous AGEs or
N
ε(carboxymethyl)lysine–modified adducts enhanced levels of mRNA and antigen for vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin. AGEs increased adhesion of polymorphonuclear leukocytes to stimulated endothelial cells in a manner reduced on blockade of RAGE.

Conclusions
—

AGEs, through RAGE, may prime proinflammatory mechanisms in endothelial cells, thereby amplifying proinflammatory mechanisms in atherogenesis and chronic inflammatory disorders.
Progression and Regression of Atherosclerotic Lesions
Authors: Helft Gérard , Worthley Stephen G. , Fuster Valentin , Fayad Zahi A. , Zaman Azfar G. , Corti Roberto , Fallon John T. , Badimon Juan J.
Published: July 2002

Background

—

Modification or stabilization of atherosclerotic plaques has been proposed as the mechanism responsible for the beneficial clinical effect of lipid-lowering therapies. An imaging modality able to quantify atherosclerotic plaque composition could potentially allow not only the identification of these vulnerable atherosclerotic lesions, but also monitoring of the effects of therapeutic interventions on plaque composition. Our aim was to monitor changes in burden and composition of atherosclerotic plaques in a rabbit model of complex atherosclerosis using serial noninvasive magnetic resonance imaging (MRI).

Methods and Results

—

Aortic atherosclerotic lesions were induced in rabbits and the animals randomized to continue an atherogenic diet (atherosclerosis progression) or resume normal chow (atherosclerosis regression) for 6 months. MRI of the aorta was performed at 3 time points in each rabbit, as follows: baseline, after atherosclerosis induction (9 months old), and after atherosclerosis regression or progression (15 months old). Histopathologic correlation with MRI was performed. There was a significant (
P
<0.0001) reduction in atherosclerotic burden in the regression group, and an increase in the progression group. There was a significant (
P
<0.001) reduction in the lipidic component of plaques in the regression group, and an increase in the progression group. A small, nonsignificant increase in the fibrotic plaque components was noted in the regression group, but a significant decrease in the fibrotic composition of lesions in the progression group. A significant correlation (
P
<0.001) was found between MRI and histopathology for atherosclerotic burden and plaque composition.

Conclusions

—

These findings indicate that serial noninvasive MRI can monitor changes in atherosclerotic plaque composition under conditions of atherosclerotic progression and regression.