bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose‐6‐phosphate dehydrogenase is involved in regulation of arterial smooth muscle phenotype in metabolic syndrome (1076.5)
Authors: Joshi Sachindra , Alloosh Muhammad , Gupte Sachin 
Published: June 2021

Rationale: Coronary artery undergoes remodeling in metabolic syndrome that increases the risk of developing cardiovascular diseases. However, the effects of metabolic syndrome in the remodeling of the coronary artery are not clearly understood. Recently we have shown that Glucose‐6‐Phosphate Dehydrogenase (G6PD) activity is involved in regulation of vascular smooth muscle phenotype. Therefore, we hypothesize that G6PD activity is involved in regulation of arterial smooth muscle phenotype in metabolic syndrome.Methods: To test this hypothesis we assayed G6PD activity in coronary arteries of pig model of metabolic syndrome (obese and lean) and in left internal mammary/radial arteries of human with metabolic syndrome (obese‐diabetic and obese‐non‐diabetic). We also assayed the markers of smooth muscle phenotype in these arteries.Results: G6PD activity was increased (P<0.05; N=3) in arteries of obese‐diabetic (0.44±0.08 nmol/min/mg protein) as compared to obese‐non‐diabetic (0.13±0.03 nmol/min/mg protein) patients. Similarly, G6PD activity was also increased (P<0.05; N=10‐12) in the arteries of obese (2.9±0.8 nmol/min/mg protein) as compared to lean (1.2±0.5 nmol/min/mg protein) pigs. Interestingly, we also found that the myosin heavy chain ‐ a gold standard marker of smooth muscle phenotype was downregulated in obese‐diabetic human and obese pig arteries as compared to arteries of obese‐non‐diabetic humans and lean pigs. Similarly, myocardin levels were also decreased.Conclusion: It appears that maladaptation of glucose metabolism and increased G6PD activity is involved in the regulation of arterial smooth muscle phenotype in metabolic syndrome.Grant Funding Source: NIHHL085352
Omental fat from obese and obese diabetic patients dys‐regulates vascular function by NF‐κB, PARP‐1 and interleukin 12‐dependent mechanism (1076.7)
Authors: Kassan Modar , Ait Aissa Karima , Haynes Bronson , Fontana Mark , Dobrian Anca , Wohlgemuth Stephen , Trebak Mohamed , Belmadani Souad , Matrougui Khalid 
Published: June 2021

Background: The abdominal adipose omental tissue in obese and obese diabetic patients is a major risk factor for cardiovascular diseases. Here we determined the role of interleukin 12 (IL‐12), NFκB and PARP‐1 in omental tissue‐induced vascular dysfunction in obese, obese type 2 diabetic (T2D) patients, and type 2 diabetic (db‐/db‐) mouse.Methods &amp; results: Mesenteric resistance arteries (MRA) from C57/BL6 and IL‐12 receptor‐/‐ mice were mounted in a wire myograph and incubated with omental fat from obese, obese T2D patients, db‐/db‐ and db‐/db‐p50NFκB‐/‐, db‐/db‐PARP‐1‐/‐ and C57/BL6 mice treated with and without NFκB (DHMQ), PARP‐1 (ABT‐888) inhibitors and IL‐12 receptor antagonist. The endothelium‐dependent relaxation was not affected. However, we observe an increase in phenylephrine‐(PE) and thromboxane‐(U46619)‐induced contraction in MRA incubated with omental fat from obese, obese T2D patients and db‐/db‐ mice. The contraction was potent with omental fat from obese T2D than obese patients. Interestingly, ABT‐888, DHMQ, IL‐12 receptor antagonist and MRA from IL‐12 receptor‐/‐ significantly reduced the exacerbated PE and thromboxane‐induced contraction in MRA incubated with omental fat from obese, obese T2D patients or db‐/db‐. Importantly, PE and thromboxane‐induced contraction was significantly reduced when MRA from db‐/db‐p50NFκB‐/‐ or db‐/db‐PARP‐1‐/‐ double knockout mice were incubated with omental fat from obese, obese T2D patients and db‐/db‐ mice. These results were associated with augmented NFkB and PARP‐1 activity and IL‐12 content in omental fat from obese, obese T2D patients and db‐/db‐ mice compared to control. IL‐12 content was significantly reduced in omental fat incubated with NFkB and PARP‐1 inhibitors.Conclusion: The present study provide evidence that adipose omental tissue in obese, obese T2D patients and T2D mouse impairs vascular function by IL‐12, NFκB and PARP‐1‐dependent mechanisms
Arterial smooth muscle cells express segment a‐deficient TMEM16A channels (1077.7)
Authors: Burris Sarah , Jangsangthong Wanchana , Leo M. Dennis , Narayanan Damodaran , Jaggar Jonathan H. 
Published: June 2021

Transmembrane protein A (TMEM16A) Cl‐ channels are expressed in arterial smooth muscle cells (SMCs) where they regulate physiological functions, including contractility and proliferation. TMEM16A alternative splice variation, which can occur at segments a, b, c, and d can alter channel biophysical properties. Identifying TMEM16A splice variants expressed in arterial SMCs should better define mechanisms by which these channels control vascular function. Our data, obtained using RT‐PCR, indicate that arterial SMCs express TMEM16A channels deficient in segment a, which removes 116 amino acids of the proximal N‐terminus. In contrast, arterial SMC TMEM16A channels contained segments b (exon 6b), c (exon13), and d (exon 15). Western blotting and whole‐cell patch clamp electrophysiology experiments demonstrated that vectors encoding segment a‐deficient TMEM16A channels (bcd) produced less protein and generated smaller whole‐cell currents than those expressing full‐length (abcd) channels in HEK293 cells. Lower TMEM16Abcd protein and currents did not occur due to attenuated transcription, elevated protein degradation or diminished surface trafficking. We are performing further experiments to test the hypothesis that segment a‐deficiency inhibits TMEM16A translation in arterial smooth muscle cells. NIH/NHLBIGrant Funding Source: NIH/NHLBI
Cardiomyocyte Ogt is essential for maintaining cardiac function (1078.1)
Authors: DeMartino Angelica , Watson Lewis , Long Bethany , Brittian Kenneth , Readnower Ryan , Brainard Robert , Cummins Timothy , Annamalai Lakshmanan , Hill Bradford , Jones Steven 
Published: June 2021

O‐GlcNAc transferase (OGT) catalyzes the post‐translational protein modification, O‐GlcNAc, in response to acute stress. We previously demonstrated a role for O‐GlcNAc in acute cardioprotection and heart failure; however, its roles in the developing heart and in the adult, non‐infarcted heart remain unknown. We hypothesized that constitutive, cardiomyocyte‐specific OGT ablation (c‐cmOGT KO) would impair cardiac function as the heart transitioned from a low afterload in utero to high as a neonate. Indeed, c‐cmOGT KO mice had impaired survival, were runted compared to littermates, had cardiomegaly, displayed marked cardiac fibrosis, and had dramatically depressed ventricular function. Histology revealed pathology in the endoplasmic reticulum (ER) and immunoblotting indicated ER stress (Grp78 and PDI) in c‐cmOGT KO hearts. Heterozygous OGT deficient mice were also generated and, unlike the acute, severe heart failure observed in the c‐cmOGT KO, heterozygous mice experienced a progressive cardiomyopathy, suggesting a potential dose‐dependent effect. Finally, we inducibly‐deleted cardiomyocyte OGT via the MerCreMer transgene. Although there were no significant defects apparent within the first few weeks, ventricular function significantly and progressively declined several weeks following deletion. These results indicate a critical, yet dynamic, role for OGT in developing and mature hearts.Grant Funding Source: Supported by the NIH and AHA
Reduction of fibrosis in type 2 diabetes by (‐)‐epicatechin (1078.4)
Authors: Peltekian Lila , Brito Alfonso , Yamazaki Katrina 
Published: June 2021

Fibrosis is the buildup of connective tissue, mainly collagen, thereby decreasing the contractility and the elasticity of the heart leading to heart failure. In this study we looked at the effects of (‐)‐epicatechin (EPI) on reducing the progression of type 2 diabetes and fibrosis in vivo. Type 2 diabetes was induced by feeding rats a high energy diet (HED) consisting of 10% lard and 20% glucose. After 4 weeks, a low dose streptozotocin (30 mg/kg) was given IP to cause partial dysfunction of pancreatic β‐cells and suppress insulin secretion. Control animals were maintained on normal chow and received an IP injection of vehicle (water). Animals were also treated with EPI (1 mg/kg/day) or water by oral gavage. Results demonstrated that diabetic animals had significant weight gain (~44%) and increased blood glucose levels (519 mg/dL) compared to control (37% and 185 mg/dL, respectively). EPI significantly reduced changes in body weight (~33%) and blood glucose levels (351.2 mg/dL) compared to diabetic animals. Histological analysis showed elevated collagen levels in diabetic hearts compared to control and EPI‐treated animals. In conclusion, our results demonstrate the ability of EPI to reduce body weight, plasma glucose levels and fibrosis in type 2 diabetes.Grant Funding Source: Support provided by CSU‐LSAMP from NSF HRD‐1302873 and Office of the Chancellor.
mTOR inhibition protects diabetic heart against ischemia/reperfusion injury through STAT3 activation (1078.5)
Authors: Das Anindita , Salloum Fadi , Durrant David , Samidurai Arun , Kukreja Rakesh 
Published: June 2021

Objective: Diabetes is a major risk factor for myocardial infarction. Rapamycin, mTOR (mammalian target of rapamycin) inhibitor, preserves cardiac function and reduces infarct size after myocardial infarction through STAT3 activation. Recent evidence showed decreased levels of activated STAT3 in diabetic heart. Considering the cardioprotective role of STAT3, we tested the hypothesis that chronic treatment with Rapamycin would protect the diabetic heart against ischemia/reperfusion (I/R) injury through STAT3 signaling.Methods and Results: Adult male wild type or db/db mice were treated daily for 28 days with vehicle (DMSO) or Rapamycin (0.25 mg/kg/day, i.p.). Following treatment, the hearts were subjected to global I (30 min) and R (1 hour) in Langendorff mode. Rapamycin treatment increased STAT3 phosphorylation, reduced infarct size following I/R (Fig. 1A), and protected adult cardiomyocytes following simulated ischemia/reoxygenation in vitro. Downstream targets of STAT3, miRNA‐17 and ‐20a, part of miRNA‐17‐92 cluster, were induced in heart (Fig. 1B, C) and cardiomyocytes derived from Rapamycin‐treated db/db mice. Rapamycin treatment also caused reduced expression of pro‐apoptotic prolyl hydroxylase Egln3/PHD3, a target of miR‐17/20a (Fig. 1D). In addition, Rapamycin‐induced protection against I/R injury was abolished in cardiac‐specific STAT3‐deficient mice made diabetic with high fat diet (Fig. 1E).Conclusion: We conclude that Rapamycin causes STAT3‐miRNA‐20a‐mediated suppression of Egln3/PHD3 that may be associated with cardioprotection against I/R injury in diabetic mice.$graphic_C467787D‐4171‐40BD‐9D1A‐4E6B545698D5$Grant Funding Source: Supported by NIH HL51045, HL79424, HL118808
Cardiac responses to GLP‐1 receptor activation are impaired in the setting of metabolic syndrome (1078.7)
Authors: Conteh Abass , Goodwill Adam , Noblet Jill , Sassoon Daniel , Tune Johnathan , Mather Kieren 
Published: June 2021

This study investigated the cardiovascular effects of the glucagon‐like peptide‐1 (GLP‐1) receptor agonist Exendin‐4 in lean vs. obese hearts. Left ventricular pressure‐volume relations were obtained following 24 hr intravenous infusion of saline‐vehicle or Exendin‐4 (30 fmol/kg/min) in lean (69 ± 4 kg) and obese (105 ± 2 kg) Ossabaw swine with metabolic syndrome (MetS). Measurements were obtained at rest, following 30 min occlusion of the left circumflex coronary artery, and following 2 hours of reperfusion. Baseline coronary flow, heart rate, and stroke volume were not different between vehicle‐treated lean and MetS swine. Exendin‐4 had no effect on end diastolic volume or stroke volume in lean or MetS swine. However, cardiac output and blood pressure were significantly increased relative to end‐diastolic filling volumes by Exendin‐4 administration in lean swine (P<0.05). Load independent assessment of cardiac inotropy revealed that Exendin‐4 increased the slope of the end systolic pressure volume relationship (ESPVR) from 2.9 ± 2.7 to 10.6 ± 2.4 mmHg/ml (p<0.05) in lean swine during ischemia. In contrast, Exendin‐4 had no effect on the relationship between cardiac output, blood pressure and end‐diastolic volume or on the ESPVR in MetS swine. These findings indicate that the cardiac inotropic actions of GLP‐1 receptor activation following ischemia/reperfusion injury are abolished in the setting of the metabolic syndrome.Grant Funding Source: Supported by NIH HL117620; NIH HL117620‐S1
Neural programming of vascular maturation and effects of denervation (1079.13)
Authors: Reho John , Zheng Xiaoxu , Benjamin James , Fisher Steven 
Published: June 2021

From birth through maturity the blood pressure in humans and animals steadily increases yet the basis of vascular maturation is unknown. The sympathetic nervous system innervates the mesenteric arterial tree post‐natally. We hypothesized that neural inputs program post‐natal maturation of regional circulations vascular smooth muscle (VSM). Chemical sympathectomy was achieved via 6‐hydroxydopamine initiated at PND1. Denervation in adult rats was achieved via disruption of the renal artery adventitia followed by a 10% phenol solution. Rat MA VSM matures from PND 12‐35 as evidenced by 1) 10‐50 fold induction of contractile protein expression via qPCR, including CPI‐17 2) 25‐50 fold induction of the α1‐adrenergic (Adra1), purinergic (P2RX1) and NPY (NPY1R) receptors that mediate VSM neural responses 3) switching of myosin phosphatase splice variant isoforms from E24‐ (LZ+) to E24+ (LZ‐). Denervation during development or in adults caused a reversion to a more immature VSM gene program. Vascular contractility via wire myography paralleled the changes in gene expression, with increased calcium sensitization during development that was inhibited by denervation. We propose that sympathetic neural inputs developmentally program MA VSM to capture control of vascular function in a feed forward manner. Removal of neural inputs programming VSM may contribute to the salutary effects of denervation in hypertension.Grant Funding Source: HL066171
Contribution of vascular hyperpolarization to augmented skeletal muscle hyperemia during hypoxic exercise in humans (1079.20)
Authors: Racine Matthew , Crecelius Anne , Larson Dennis , Luckasen Gary , Dinenno Frank 
Published: June 2021

Exercise hyperemia during hypoxia is augmented relative to normoxia. At moderate exercise intensities, nitric oxide (NO) and vasodilating prostaglandins (PGs) explain ~50% of this response, yet the remaining signaling mechanisms remain unclear. We hypothesized that vascular hyperpolarization via activation of inwardly rectifying potassium (KIR) channels and Na+/K+‐ATPase accounts for the remaining ~50% of the augmented hyperemia. In 10 young adults, we measured forearm blood flow (FBF; Doppler ultrasound) during 5 min of rhythmic handgrip exercise at 20% maximal voluntary contraction in normoxia (NormEx) and isocapnic hypoxia (HypEx; O2 saturation 80%) before and after local combined inhibition of NO synthase (L‐NMMA), cyclooxygenase (ketorolac), KIR channels (barium chloride) and Na+/K+‐ATPase (ouabain). All trials were performed during local α‐ and β‐adrenoceptor blockade to isolate local vasodilation. In control conditions, FBF during HypEx was augmented vs. NormEx by 62±8 ml/min (P<0.05). In the blocked condition, this compensatory increase in FBF was only 29±6 ml/min (47±10% decrease), but O2 extraction was increased to maintain forearm VO2. These findings are similar to our previous observations with combined inhibition of NO and PGs alone, suggesting that vascular hyperpolarization via these pathways does not contribute to the augmented hyperemic response during hypoxic exercise.Grant Funding Source: Supported by NIH award HL‐095573 (FAD)
The heart as an endocrine source of metabolic vasodilators (1079.26)
Authors: Kang Patrick , Chen Chwen‐Lih , Ohanyan Vahagn , Bratz Ian , Meszaros J. , Chilian William , Chen Yeong‐Renn 
Published: June 2021

During heightened cardiac work, O2 consumption by the heart increases. This increase benefits energy production via mitochondrial e¯ transport, but the process of e¯ transport is not perfect and some e¯ “leak” from respiratory chain and reduce O2. This reduction yields O2˙¯, which reacts with thiol groups, iron, and is rapidly metabolized into H2O2 by mitochondrial superoxide dismutase (SOD2). To understand the potential systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac specific SOD2 overexpression, which would increase the amount of H2O2 produced by the heart. To determine if this enhanced production of H2O2 results in a humoral action, i.e., systemic vasodilation, we first evaluated the effectiveness of SOD2 overexpression to effectively remove O2˙¯ from the mitochondria (EPR). SOD2 transgenic mice produced less O2, and had lower redox activity. Mitochondria of SOD2‐tg (vs WT) had lower GSSG concentration (decreased by 37.2±4.5%, GSH/GSSG ratio was increased by 66.7±6.8%). EPR analysis of the isolated mitochondria showed significant decrease of semiquinone in the SOD2‐tg vs WT at the Qi site (by 69.4±9.9%), and a diminished complex I protein thiyl radical(s) in the mitochondria of SOD2‐tg. These results support a more reducing milieu in the mitochondria of the SOD2‐tg heart. Cardiac mitochondria isolated from SOD2‐tg exhibited no significant differences in the respiratory control index between WT and SOD2‐tg (6.30.3 vs. 5.70.5, p>0.05). These results support the concept that the SOD2 overexpression is effective and results in increased production of H2O2. Moreover, arterial pressure was lower in the SOD2‐tg, but was normalized by iv injection of catalase, implying that the metabolic dilator, H2O2, “spilled” over inducing systemic vasodilation. In conclusion, SOD2 overexpression in myocytes triggers a more reductive milieu in murine heart enhancing the production of H2O2, which then acts as an endocrine dilator causing reductions in arterial pressure.Grant Funding Source: NIH RO1 HL083237
Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries (1079.7)
Authors: Springo Zsolt , Toth Peter , Tarantini Stefano , Tucsek Zsuzsanna , Cseplo Peter , Koller Akos , Sonntag William , Csiszar Anna , Ungavri Zoltan 
Published: June 2021

Stability of myogenic tone of cerebral arteries is essential for adequate control over penetration of pressure (P) waves into the distal portion of the cerebral microcirculation (the resistance to flow is dominated by the fourth power of the internal vessel radius). Because aging promotes cerebromicrovascular injury, we tested the hypothesis that aging alters the myogenic response. P‐induced constriction of cannulated middle cerebral arteries (MCA) isolated from young (3 mo) and aged (24 mo) mice was assessed. Both young and aged MCAs developed similar myogenic tone in response to stepwise, steady‐state increases in intraluminal P. Young MCAs exhibited significant myogenic adaptation to sinusoidal pulsatile P (amplitude: 40 mmHg, freq:450/min). While in myogenically inactive MCAs each P pulse elicited a ~7% distension in synchrony with the pulsatile P, in young myogenically active MCAs the amplitude of the diameter changes induced by the P pulses in the autoregulated P range was significantly attenuated (~2%). The mean P‐myogenic tone curve was similar in young MCAs exposed to constant and pulsatile P. In aged MCAs the cyclic changes in diameter induced by the P pulses were increased (~4%) and development of myogenic tone in response to pulsatile P was impaired. Collectively, aging impairs myogenic adaptation of cerebral arteries to pulsatile P, which likely promotes the development of cerebral microbleeds and BBB disruption by allowing high P to penetrate the distal portion of the cerebral microcirculation.Grant Funding Source: Supported by TÁMOP 4.2.4.A/2‐11‐1‐2012‐0001,SROP‐4.2.2.A‐11/1/KONV‐2012‐0024 and 0017,OTKA K‐108444
Levosimendan preserves systolic and diastolic function in rats with volume overload heart failure through myofilament Ca2+ sensitization and regulatory protein phosphorylation (1081.4)
Authors: Lewis Kristin , West T. , Zhang Xiaojin , Trask Aaron , Cismowski Mary , de Tombe Pieter , Sadayappan Sathivel , Lucchesi Pamela 
Published: June 2021

Objectives. This study investigated whether early intervention with the myofilament Ca2+ sensitizer levosimendan (Levo) could preserve cardiac function in aortocaval fistula (ACF)‐induced volume overload (VO). Methods and Results. ACF or sham surgery was performed in male Sprague‐Dawley rats (200‐240g) 4 weeks prior to initiating treatment with Levo (1 mg/kg/day in drinking water) or vehicle (Veh; water) for 4 weeks. Even with continued VO and compared with ACF‐Veh, Levo improved systolic (%FS, Ees, PRSW; 41.3 vs 32.2%, p<0.0001; 0.654 vs 0.392 mmHg/µL, p<0.05; 113.6 vs 60.2 mmHg, p<0.05, respectively) and diastolic (tau, dP/dtmin; 8.9 vs 10.8 msec, p<0.05; ‐7626 vs ‐5739 mmHg/sec, p<0.001, respectively) function without significant LV remodeling. Additionally, Levo treatment resulted in 1) improved myofilament Ca2+ sensitivity without significantly affecting the amplitude and kinetics of the myocyte intracellular Ca2+ transient; 2) preserved in vivo β‐adrenergic responsiveness; and 3) increased phosphorylation of cMyBP‐C Ser‐273 and Ser‐302 and cTnI Ser‐23/24 that was associated with the improved diastolic function. Levo did not increase α‐MHC/β‐MHC mRNA compared with Veh. Conclusion. These results demonstrate that myofilament regulation in VO HF preserves systolic and diastolic function and may provide a new therapeutic target in patients with volume overload heart failure.Grant Funding Source: Supported by: R01 HL‐056046 (to PAL), R01 HL‐62426 (to PDT), R01 HL105826 and K02 HL 114749 (to SS)
Oxidative stress‐induced changes in nitric oxide availability contribute to increased pulmonary microvascular tone in a mouse model of Alzheimer's disease (1082.2)
Authors: Roberts Andrew , Jagadapillai Rekha , Vaishnav Radhika , Friedland Robert , Sachleben Leroy , Gozal Evelyne 
Published: June 2021

Inflammation and oxidative stress are well‐known components of Alzheimer's disease (AD) that cause cardio‐respiratory abnormalities. To determine if AD‐induced inflammation occurs in the lung and affects its function, we hypothesized that these processes of AD cause pulmonary microvascular dysfunction by decreasing lung nitric oxide (NO) bioavailability. We assessed pulmonary involvement in an established mouse transgenic AD model expressing the human APP gene 770 isoform with the Swedish, Dutch and Iowa mutations, and in wild type (WT) controls. Mice 7‐20 months old were used, since at these ages AD model mice have microvascular injuries. Effects of acute NO synthase (NOS) inhibition with L‐NAME on pulmonary microvascular diameter were examined in the right lung of anesthetized, open chest AD and WT mice by intravital microscopy while the lungs were statically inflated with O2. Arteriolar constriction to L‐NAME was blunted in AD mice compared to WT controls. Lung immunohistochemistry showed a significant increase in superoxide production and inducible NOS (iNOS) in the AD model mice. Our data suggest that despite iNOS induction, superoxide formation decreases lung NO bioavailability in AD, resulting in changes in pulmonary vascular tone. The loss of this vasodilator influence indicates cardiovascular dysfunction may be initiated in AD through a generalized inflammatory process.Grant Funding Source: Supported by AG017173 to RPF