bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE 2: A potential therapeutic target for Angiotensin II‐mediated insulin resistance and glucose intolerance
Authors: Chhabra Kavaljit H. , Xia Huijing , Lazartigues Eric 
Published: June 2021

Over activation of the renin‐angiotensin system (RAS) plays a key role in diabetes. ACE2 has been reported to counteract the pathophysiological effects of RAS over activity. To clarify the role of ACE2 in glucose homeostasis, ACE2 KO and control mice (5 months old, n=5/group) were infused with AngII (osmotic pump: 600 ng/kg/min); insulin levels (ng/ml) and glucose tolerance (AUC: mg/dl*120) were assessed after 14 days infusion. KO mice manifested significantly (P<0.05) higher hyperinsulinemia (6.2 ±0.49 vs. 4.5 ±0.23) and glucose intolerance (55300 ±1387 vs. 43550 ±1735) compared to controls, suggesting their hypersensitivity to diabetes. To assess the therapeutic potential of ACE2, βTC‐ 3 cells (mouse insulinoma) were subjected to glucose stimulated insulin secretion assay (2.8, 16, 25 mM glucose) in which AngII significantly (P<0.05) decreased insulin secretion vs. control group (1.01 ±0.01 vs. 1.84 ±0.12; 1.57 ±0.15 vs. 2.78 ±0.05; 1.7 ±0.08 vs. 2.64 ±0.05 ng/ml, respectively). In cells pretreated with an adenovirus over expressing ACE2, insulin secretion was restored (1.75 ±0.14; 2.81 ±0.22; 3.25 ±0.22 ng/ml, respectively), suggesting ACE2 can prevent the Ang‐II mediated inhibitory effect. In conclusion ACE2 is important in the regulation of glucose homeostasis and could be a potential therapeutic target to ameliorate insulin resistance and glucose intolerance resulting from RAS over activation.LSUHSC research enhancement fund.
Endothelium‐dependent contractions induced by aging and diet‐induced obesity are attenuated in lipocalin‐2 deficient mice
Authors: Liu Jacky TC , Xu Aimin , Man Ricky YK , Mak Tak W , Law Ivy KM , Liang CF , Vanhoutte Paul M , Wang Yu 
Published: June 2021

AimLevels of Lipocalin‐2, a pro‐inflammatory adipokine, correlates with adiposity, dyslipidemia, hyperglycemia and insulin resistance. The present study evaluates vascular function in mice with deletion of the lipocalin‐2 gene (Lcn2‐KO).MethodsWild type (WT) and Lcn2‐KO mice were fed with standard or high fat diet for 3–17 weeks. Intra‐arterial blood pressure was measured. Isometric tension was measured in carotid artery rings with or without endothelium. Protein expression was measured by Western blotting.ResultsThe obesity‐induced increase in systolic blood pressure was attenuated in Lcn2‐KO mice. In aged or obese WT mice, acetylcholine (ACh)‐elicited endothelium‐dependent contractions were abolished by the COX‐1 selective inhibitor SC560 and the NADH oxidase inhibitor diphenylene iodonium. These contractions were attenuated in Lcn2‐KO mice. ACh‐stimulated superoxide anion production, COX‐1 mRNA and protein expression were decreased in Lcn2‐KO arteries. ACh‐induced production of prostacyclins (PGI2) was lower in Lcn2‐KO preparations. In aged or obese WT mice, PGI2 caused contractions in rings without endothelium but these contractions were reversed to relaxations in Lcn2‐KO arteries.ConclusionsLipocalin‐2 plays an important role in obesity‐induced hypertension and endothelial dysfunction through production of superoxide anions and COX‐1 expression.
Inhibition of Vasoconstriction by Amlodipine in Human Internal Mammary Arteries Used as Bypass Grafts
Authors: HE Guo‐Wei , BAI Xiao‐Yan , LIU Xiao‐Cheng , JING Wen‐Bin , FAN Li , YANG Qin 
Published: June 2021

Graft spasm remains challenging in coronary artery bypass grafting (CABG). We studied the inhibitory effect of a dihydropyridine calcium antagonist amlodipine in 70 human internal mammary artery (IMA) segments from 34 patients undergoing CABG in organ baths in two ways: the relaxing effect of amlodipine on vasoconstrictor‐induced precontraction by potassium chloride (KCl), human urotensin II (hU‐II), and U46619 and the depressing effect of amlodipine on the contraction. Amlodipine caused full relaxation in KCl (98.0±2.1%)‐ and hU‐II (98.5±2.4%)‐ but not in U46619‐contracted IMA rings (n=8) with 15.5‐fold higher potency to KCl than to hU‐II (EC50: −8.17±0.28 vs. −6.98±0.01 logM, p<0.001). Pretreatment of IMA with plasma‐concentrations of amlodipine (−7.6 and −6.6 logM, n=6) significantly depressed subsequent contraction to KCl (from 20.8±2.5 to 16.6±2.6 mN and from 20.8±2.5 to 7.6±3.0 mN, p<0.05) and hU‐II (from 14.1±4.2 to 11.4±3.7 mN and from 14.1±4.2 to 3.8±2.0 mN, p<0.05) but not to U46619. Thus, in human IMA, amlodipine has a selective inhibitory effect on the vasoconstriction mediated by vasoconstrictors with high potency on KCl and hU‐II and amlodipine may be effectively used in CABG patients for treatment and prevention of graft spasm.Supported by Tianjin Municipal Sci & Tech Com (09ZCZDSF04200); Ministry of Sci & Tech, China (2009DFB30560); Providence SVMF, OR & Hong Kong GRF 465107, 478909.
The anti‐atherogenic potential of C‐type natriuretic peptide: Disparate regulation of endothelial and vascular smooth muscle cell proliferation via natriuretic peptide receptor‐C
Authors: Khambata Rayomand S , Panayiotou Catherine M , Xiao Fang , Hobbs Adrian J 
Published: June 2021

C‐type natriuretic peptide (CNP) is an endothelium‐derived mediator that exerts an anti‐atherosclerotic influence on the blood vessel wall. Herein, we examined whether the cytoprotective activity of CNP might be mediated, in part, via opposing effects on endothelial and vascular smooth muscle cell proliferation.CNP increased human umbilical vein endothelial cell (HUVEC) proliferation but inhibited rat aortic smooth muscle cell (RAoSMC) growth; both effects were blocked by the selective natriuretic peptide receptor (NPR)‐C antagonist M372049 and the extracellular signal regulated kinase (ERK) 1/2 inhibitor PD98059. The effects of CNP on cell proliferation were also lost in endothelial and vascular smooth muscle cells from NPR‐C knockout mice. In both HUVEC and RAoSMC, CNP caused ERK 1/2 phosphorylation in a M372049‐inhibitable manner. In HUVEC, CNP‐dependent ERK 1/2 activation resulted in enhanced expression of the cell cycle promoter, cyclin D1, and concomitantly decreased expression of the cell cycle inhibitor, p21. In contrast, in RAoSMC ERK 1/2 activation by CNP was accompanied by increased expression of the cell cycle inhibitors p21 and p27.These data show that CNP can up‐regulate endothelial cell proliferation yet inhibit vascular smooth muscle cell growth via the same receptor, NPR‐C. Such findings highlight further the anti‐atherogenic ability of CNP.Funded by the Wellcome Trust
Famous & Outstanding Anatomy Professors I Have Known or with Whom I Have Taught
Authors: Clemente Carmine 
Published: June 2021

The first two outstanding anatomists I wish to discuss are William Frederic Windle and Horace Winchell Magoun, both students of Stephen Walter Ranson in Chicago.I became acquainted with Bill Windle 60 years ago in 1949 while he was Chairman of Anatomy at the University of Pennsylvania. He interviewed me before my being accepted into graduate school at Penn and his principal question was, “Are you a good student?” I told him that I received A's and B's during my four years at Penn. He replied that is not good enough. He required all A's during the first two graduate school years. His next question was, “Do you have a microscope?” My brother had graduated from the Penn Medical School and I said I'm sure I could get his microscope. Then Dr. Windle said, “Come around in September. We will find a place for you.”I will talk also about my interaction with Professor Horace Magoun who offered me my first job at UCLA. He became my close friend, often advising me through the early years of my academic life.Giving my first paper to the AAA in Detroit, Michigan in 1951 after my second graduate school year, I was nervous and scared. When I started my talk. I noticed that in the audience was the famous Horace Magoun, the discoverer of the Reticular Activating System in the brain stem, responsible for maintaining wakefulness behavior. Later that day I was stunned when he asked me if, when I finished at Penn, I would consider joining him at Los Angeles where UCLA had just opened its medical school.Over the years I also met or taught with such famous professors as John Boilieu Grant, Raymond Jack Last and Oscar Vivian Batson.
Cellular junction remodeling underlies the role for the planar cell polarity pathway in directional cochlear extension
Authors: Chen Ping , Ren Dongdong , Chacon‐Heszele Maria , Kelly Micahel C , Qian Dong 
Published: June 2021

The mammalian hearing organ, the organ of Corti, is suspended along the spiraled cochlear duct and consists of stereotypical arrays of uniformly oriented sensory hair cells interdigitated with supporting cells. During development, postmitotic precursor cells of the organ of Corti undergo cellular rearrangement, resulting in its extension as well as precise patterning of sensory and non‐sensory cells and uniform orientation of hair cells. It is thought that the vertebrate planar cell polarity (PCP) pathway regulates both the cellular rearrangement for the extension of the organ of Corti and the uniform orientation of sensory hair cells.The objectives of this study are to characterize cellular behavior and morphology during terminal differentiation of the organ of Corti, and to investigate the mechanism underlying cellular rearrangements for the extension of the organ of Corti.We examined cellular geometry, cellular contacts and junctions in the wild‐type developing organ of Corti. We also examined the development of the organ of Corti in mouse mutants defective in an adheren junction component, p120, or in an essential PCP component, Vangl2. We are carrying out live imaging to record cellular behavior and geometric change during terminal differentiation of the organ of Corti in culture.Our results show that the developing organ of Corti undergoes unique cellular intercalation for its directional extension. Proper remodeling of cell‐cell junctions is required for cochlear extension, and the role for the PCP pathway in cochlear extension is likely mediated by cell adhesion molecules and independent of the role for PCP pathway in hair cell orientation.
Mitochondrial Depolarization Is Not responsible for Cardioprotection During Ischemic Preconditioning
Authors: Lee Daniel , Quarrie Ricardo , Cramer Brandon , Steinbaugh Gregory , Pfeiffer Douglas R , Zweier Jay L , Crestanello Juan A 
Published: June 2021

Mitochondrial (mito) respiratory electron transfer chain (RTC) is a major source of reactive oxygen species (ROS) during ischemia reperfusion (IR). Mito membrane potential (Δψ) may affect ROS production by changing the redox status of the RTC. Mild uncoupling can lead to oxidation of the RTC and decrease ROS production. It is unclear how ischemic preconditioning (IPC) decreases mito ROS generation. We examined the changes in mito Δψ and its correlation to ROS production in IR and IPC mito.Isolated rat hearts (n=6/group) were subjected to 1) CONTROL: 30 minutes (min) of equilibration (EQ), 30 min of ischemia (I), and 30 min of reperfusion (RP), or 2) IPC: 10 min of EQ, two 5 min episodes of I and RP, 30 min of I, and 30 min of RP. Mitos were isolated at end I and end RP. ROS production was assessed by EPR spectroscopy using DMPO as spin trap. Δψ was measured using a TPP electrode. Data is expressed as mean±sem.

ROS production by Complex I & III (arbitrary units/mg protein)
Δψ (‐mV)

End I
End RP
End I
End RP

CONTROL
2220±22
3524±340
121±8
150±2

IPC
1878±175
2479±296*
147±7*
160±3*

p<0.05 vs. CONTROL

Ischemia led to lower Δψ in IPC and CONTROL. Δψ recovered during reperfusion. However, Δψ remained higher in IPC at end I and end RP. IPC decreases ROS production during RP. Membrane depolarization was not associated with lower ROS production. We conclude that membrane depolarization is not responsible for the cardioprotective effect of IPC.
Interstitial nitric oxide concentrations are elevated in rat gastrocnemius muscle following recovery from femoral occlusion
Authors: Fabris Sergio , Smith Ashley A , Parlett Brittney , MacLean David A 
Published: June 2021

The present study examined the effects of ischemia‐reperfusion on the interstitial levels of nitric oxide (NO) and adenosine (Ado). Eight anesthetized rats had two microdialysis fibers inserted into the gastrocnemius muscle of each leg and perfused with Ringers (control) or 500 μM AOPCP (5'ectonucleotidase inhibitor). Following baseline collections both femoral arteries were clamped for 60 min (samples at 20, 40 and 60 min) and then released (samples at 20 min). With Ringers perfusion there were no increases in interstitial NO (baseline = 4.2±0.4 μM) during ischemia but NO was elevated (P<0.05) following reperfusion (5.4±0.5 μM). Prior to occlusion AOPCP treatment resulted in an increase (P<0.05) in NO from 4.3±0.6 to 5.5±0.5 μM as compared to Ringers. No further increases in NO were observed with AOPCP during ischemia, but NO was further elevated (P<0.05) following reperfusion (6.5±0.6 μM). Interstitial NO concentrations were higher (P<0.05) during AOPCP treatment compared to Ringers at all time points. There were no changes in interstitial Ado during the study. These data show that NO and Ado are not altered during femoral occlusion, but NO is elevated during reperfusion and that NO is even higher during ischemia‐reperfusion when Ado production is inhibited. These findings suggest that NO plays an important role in interstitially mediating vasodialtion during skeletal muscle reperfusion.Supported by NSERC
Nuclear factor‐ kappa B expression and matrix metalloproteinase activity in hypertension
Authors: Wu Kwan‐I , Schmid‐Schönbein Geert W. 
Published: June 2021

Our recent evidences suggest that inflammation of the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor NF‐κB is overexpressed in the SHR and involved in the overexpression of MMPs.NF‐κB expression level and translocation were compared between Wistar Kyoto rat and SHR kidney, heart, and brain. In addition, the animals were treated with a NF‐κB inhibitor, pyrrolidine dithiocarbamate (PDTC), for ten weeks. To determine the correlation between NF‐κB and MMP, MMP‐2 and −9 activities were examined after treatment.Immunohistochemistry showed that NF‐κB expression is significantly increased in SHR in renal glomerular and tubulointerstitial areas and brain hypothalamus compared to that in WKY (p<0.05), but not in myocardium and cerebral cortex. Significant NF‐κB translocation into the nucleus was found in renal tubular cells, cardiac muscle cells, and arterioles of kidney and brain in SHR.After PDTC treatment, the systolic blood pressure in SHR was suppressed by 36 % as compared to no significant difference in WKY rats. NF‐κB expression level in treated‐SHR was also decreased in renal glomerular and tubulointerstitial areas and hypothalamus compared to non‐treated animals (p <0.05). Furthermore, MMP‐2 activity was significantly reduced by PDTC treatment in both WKY and SHR. The enhanced MMP‐9 activity in SHR was also significantly decreased by PDTC (p <0.01). These results suggest NF‐κB is an important transcription factor in the SHR and may be responsible for its enhanced MMP activity.Supported by HL 10881
Short term STZ‐induced diabetes reduced left ventricular dysfunction and promoted morphometric, immune and antioxidant adaptations after myocardial infarction in rats
Authors: Candido Georgia Orsi , Mendes Roberta Hack , Rodrigues Bruno , Rosa Kaleizu Teodoro , de Souza Leandro Ezequiel , Di Petta Antonio , Sammoniya Paulina , Belló‐Klein Adriane , De Angelis Kátia , Irigoyen Maria Claudia 
Published: June 2021

We verified if left ventricular (LV) dysfunction induced by myocardial infarction (MI) in STZ‐diabetic rats was related to collagen deposition, inflammatory response and antioxidant enzymes profile. Male Wistar rats were divided: Control (C), Diabetes (D), MI (I) and diabetes +MI (DI). MI area was similar between I (36±6%) and DI (30±4%) groups at the end of protocol (5 days after MI surgery). However, ejection fraction (I: 38±4 vs. DI: 48±5%), fractional shortening (I: 25±2 vs. DI: 37±2%), and E/A ratio were improved in DI in comparison with I rats. Collagen (by picrosirius red stain) (25%) and myocardium inflammatory cells quantifications (by Hematoxin‐Eosin) (71%) was reduced in DI as compared with I animals; while heart antioxidants superoxide dismutase (25%) and catalase (10%) were increased in DI when compared to I rats. In addition, a positive correlation was observed between collagen and inflammatory cells quantifications (r=0.7; p<0.0001) in all groups. This study showed that the attenuation of LV dysfunction observed in DI rats is probably due to a compensatory mechanism associated with morphometric and immune adaptations, as well as an increase of antioxidant enzymes activity. These data suggest an important role of heart glucose availability in myocardial protection after an ischemic event.FAPESP
Imidazolines as single agent therapy for diabetics with hypertension
Authors: Edwards Lincoln Paul , Crane Louis , Baziard‐Mouysset Genevieve , Brown‐Bryan TerryAnn 
Published: June 2021

Pharmacologic treatment of many diabetics also involves treating hypertension. This requires taking multiple drugs, which increases the risk of drug interaction, and decrease compliance and glycemic control. Imidazoline compounds have the potential to act as single agent therapy to treat diabetics with hypertension, thereby positively impacting compliance. We hypothesize that imidazoline compounds act centrally to lower blood pressure and decrease hyperglycemia by stimulating glucose uptake.Moxonidine (5nmol) and S43126 (5nmol), were injected cumulatively into the brain of spontaneously hypertensive rats, followed by measurement of blood pressure. HEK 293 kidney cells were treated with moxonidine (1μM) and glucose uptake measured. The imidazoline receptor antisera selective (IRAS) protein was overexpressed in HEK 293 cells, followed by treatment with moxonidine. Western blot was used to determine the phosphorylation of protein kinase B.Our results showed that both S43126 and moxonidine lowered arterial pressure by 20mmHg and 45mmHg respectively. Moxonidine caused a greater than 6 fold increase in glucose uptake at 60 min of treatment in HEK 293 cells. Cells overexpressing the IRAS protein showed a greater phosphorylation of PKB after treatment with moxonidine.These data suggest that imidazoline compounds may be developed as alternative therapy to treat diabetics with hypertension.
The role of P2Y2 receptor activation in pro‐fibrotic responses of cardiac fibroblasts
Authors: Lu David , Braun Oscar Ö. , Aroonsakool Nakon , Insel Paul A. 
Published: June 2021

Cardiac fibroblasts (CFs) play an essential structural role in the heart and in cardiac remodeling after injury. CFs are activated and adopt a pro‐fibrotic phenotype in response to a variety of growth factors including extracellular nucleotides. Such nucleotides can interact with 8 known P2Y receptors, G‐protein‐coupled receptors (GPCRs); P2Y2 receptors (P2Y2R), which are activated by ATP and UTP, are the most abundant P2Y receptor expressed by rat cardiac fibroblasts. In this study we examined the effect of UTP on fibroblast transformation. UTP dose‐dependently increased the expression of pro‐fibrotic markers, including plasminogen activator inhibitor‐1, transforming growth factor‐ß and α‐smooth muscle actin. In addition, UTP increased proliferation and migration of CFs. Effects similar to those induced by UTP occurred with the non‐hydrolyzable analog UTPγS. The stimulatory effects of UTP on pro‐fibrotic gene expression and CF proliferation did not occur in CF from P2Y2R‐knockout mice. Thus, UTP promotes CF transformation to a pro‐fibrotic phenotype through activation of P2Y2R. Our results suggest that UTP and other extracellular nucleotides (e.g. ATP) may act via P2Y2R to regulate CF activation and migration during normal and injury‐induced cardiac remodeling.Supported by grants from NIH (GM007752, HL066941, GM066232) and the Ellison Medical Fdn.
Mitigation of Heart Failure Progression with Sildenafil Involves Inhibition of RhoA/Rho‐Kinase Pathway
Authors: Salloum Fadi N , Chau Vinh Q , Hoke Nicholas N , Abbate Antonio , Kukreja Rakesh C 
Published: June 2021

Chronic inhibition of phosphodiesterase‐5 (PDE‐5) with sildenafil after permanent occlusion of the left anterior descending coronary artery (LAD) limits ischemic heart failure (HF) in mice. We postulated that treatment with sildenafil beginning at 3 days post myocardial infarction (MI) would also attenuate HF through inhibition of RhoA/Rho kinase pathway.Adult male ICR mice with fractional shortening (FS) less than 25% at day 3 following permanent LAD ligation were treated with either saline (volume matched, ip, BID) or sildenafil (21 mg/kg, ip, BID) for 25 days. Echocardiography showed FS preservation and less left ventricular dilatation with sildenafil treatment versus saline at 7 and 28 days post‐MI (P<0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and TUNEL, respectively, were attenuated with sildenafil (P<0.05 vs. saline). Western blotting showed enhanced Bcl‐2/Bax ratio with sildenafil (P<0.05 vs. saline). Activity assay showed sildenafil‐mediated PKG activation 1 day after treatment (P<0.05 vs. sham and saline). Activation of PKG with sildenafil was associated with inhibition of Rho kinase (P<0.05), as compared to saline.Our findings show that chronic sildenafil treatment in mice with HF attenuates LV dysfunction independent of its infarct‐sparing effect by inhibiting the RhoA/Rho kinase pathway. This research was funded by NIH (HL51045, 79424 and 93685 to RCK).
Dihydrotestosterone attenuates HIF‐1alpha and COX‐2 in cerebral arteries following hypoxia.
Authors: Osterlund Kristen Leanne , Handa Robert J , Gonzales Rayna J 
Published: June 2021

Vascular inflammation is under the control of several transcription factors, one of which is hypoxia inducible factor‐1 alpha (HIF‐1α). HIF‐1α activation can lead to the production of inflammatory mediators such as cyclooxygenase‐2 (COX‐2). This study determined the influence of dihydrotestosterone (DHT) on HIF‐1α and COX‐2 following hypoxia. COX‐2 and HIF‐1α protein levels were assessed in cerebral arteries isolated from castrated rats treated with DHT (3 wk) in vivo and exposed to normoxia or hypoxia (1%; 6h) ex vivo and in primary human brain vascular smooth muscle cells pretreated with vehicle or DHT (100nM; 18h) and exposed to hypoxia and glucose deprivation (1% O2; 0 or 6h). Under normoxic conditions, DHT increased COX‐2 levels but had no effect on HIF‐1α protein levels and HIF‐1α DNA‐binding was below the level of detection. Following hypoxia or hypoxia and glucose deprivation, HIF‐1α and COX‐2 levels were increased; this response was blunted in the presence of DHT. In addition, increases in HIF‐1α DNA‐binding following hypoxia (1%; 1h) were reversed by DHT. In conclusion, under hypoxic conditions, the blunted response of COX‐2 by DHT may involve HIF‐1α activation. In contrast, the effect of DHT to increase COX‐2 under normoxic conditions may be independent of the HIF‐1α pathway.AHA SDG RG, AHA Predoctoral Fellowship KO