Coronary vasodilation mediated by T cells expressing choline acetyltransferase

This study shows ChAT-expressing T cells can induce vasodilation of the blood vessel in the coronary circulation and that this effect relies on a direct interaction between T cells and the coronary vascular endothelium. The study establishes a potential immunomodulatory role for T cells in the coronary circulation. The present findings offer an additional possibility that a deficiency of ChAT-expressing T cells could contribute to reduced coronary blood flow and ischemic events in the myocardium.

Adenosine and adenosine receptor-mediated action in coronary microcirculation

Adenosine is an ubiquitous extracellular signaling molecule and plays a fundamental role in the regulation of coronary microcirculation through activation of adenosine receptors (ARs). Adenosine is regulated by various enzymes and nucleoside transporters for its balance between intra- and extracellular compartments. Adenosine-mediated coronary microvascular tone and reactive hyperemia are through receptors mainly involving A2AR activation on both endothelial and smooth muscle cells, but also involving interaction among other ARs. Activation of ARs further stimulates downstream targets of H2O2, KATP, KV and KCa2+ channels leading to coronary vasodilation. An altered adenosine-ARs signaling in coronary microcirculation has been observed in several cardiovascular diseases including hypertension, diabetes, atherosclerosis and ischemic heart disease. Adenosine as a metabolite and its receptors have been studied for its both therapeutic and diagnostic abilities. The present review summarizes important aspects of adenosine metabolism and AR-mediated actions in the coronary microcirculation.

Progesterone modulates endothelium-dependent coronary vascular reactivity in SHR

Although progesterone has the ability to promote dilation of vascular smooth muscle, its role in coronary circulation is still poorly characterized, especially in essential hypertension and in a model of endogenous deficiency of ovarian hormones. Thus, this study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in hypertensive (SHR) and ovariectomized rats. Adult SHR aged 8 to 10 weeks were divided into: SHAM, Ovariectomized (OVX) and Ovariectomized + treatment with 2 mg/kg/day of progesterone for 15 days (OVX-P4). Coronary vascular reactivity was investigated using modified Langendorff method. After stabilization, baseline coronary perfusion pressure (CPP) was recorded and vascular reactivity to bradykinin (BK, 0.1-1000 ng) assessed before and after infusion, either individually or in combination, with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin or clotrimazole. Scanning electron microscopy was used for qualitative analysis of the endothelium. OVX and OVX-P4 groups had a higher baseline CPP compared to that of the SHAM group. BK was able to promote vasodilation in all groups. However, relaxation to BK was less pronounced in the OVX group when compared to SHAM, with architecture loss and areas of cell atrophy having been observed. Progesterone treatment prevented this injury. Perfusion with L-NAME induced greater damage to the SHAM group, while the use of indomethacin led to a significant reduction in the vasodilator response to BK in the OVX-P4 group. Taken together, our results show that progesterone modulates endothelium-dependent coronary vasodilation in SHR ovariectomized, preventing damage caused by ovarian hormonal deficiency through a mechanism that involves prostanoid pathway.

Abstract 17248: The Role of microRNA-21 in Regulating the Coronary Microcirculation in Diabetes

Introduction: Coronary microvascular dysfunction is prevalent among diabetics and intersects with deficits in endothelial-dependent vasodilation. These deficits occur early in the progression of the disease, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelial-dependent mediator of vasodilation in the healthy coronary circulation, but the mediator switches to hydrogen peroxide (H 2 O 2 ) in coronary artery disease (CAD) patients. Diabetes is a risk factor for CAD, so we hypothesized that a similar switch would occur. Methods: Coronary arteries were isolated and endothelial-dependent vasodilation was assessed using myography. Quantitative polymerase chain reaction (qPCR) was performed for gene expression analysis and myocardial blood flow (MBF) was measured by contrast echocardiography. Results: Nitric oxide synthase inhibitor (L-NAME) inhibited vasodilation in wild type (WT) mice, but the H 2 O 2 scavenger (PEG-catalase) had no effect. In contrast, vasodilation in diabetic mice was blunted by PEG-catalase, but not L-NAME. This suggests that the mediator of coronary vasodilation switched from NO to H 2 O 2 in diabetes. Importantly, we found that microRNA-21 (miR-21) is upregulated in diabetes and the deficiency modulates the mediator switch from NO to H 2 O 2 in diabetic mice. Conclusions: The switch in the mediator of coronary vasodilation from NO to H2O2 contributes to microvascular dysfunction in diabetes and miR-21 regulates this switch. Further genetic profiling will elucidate the pathways and mechanisms converging with miR-21 to regulate microvascular function in diabetes. This is the first mouse model that recapitulates the switch in mediator of coronary vasodilation from NO to H 2 O 2 seen in CAD patients.

Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries

Background Voltage-gated K+ (Kv) channels in coronary artery smooth muscle cells (CSMCs), especially the major specific Kv1 subfamily, contribute to coronary artery vasodilation. Advanced glycation end products (AGEs) have been strongly implicated in diabetes-related cardiovascular complications. Our previous study showed AGEs can impair Kv channel-mediated coronary vasodilation by reducing Kv channel activity. However, its underlying mechanism remains unclear. Purpose Here, we used isolated rat small coronary arteries (RSCAs) and primary CSMCs to investigate the effect of AGEs on Kv channel-mediated coronary vasodilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR)-γ pathway. Methods RSCAs and primary CSMCs were isolated, cultured and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO) and/or GW9662, and then divided into the following groups: DMEM, BSA, AGE, AGE+ALA, AGE+PIO, and AGE+PIO+GW9662. Kv channel-mediated coronary vasodilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, the major Kv1 channel subunits expressed in CSMCs (Kv1.2/1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). Results AGEs markedly reduced forskolin-induced Kv channel-mediated vasodilation of RSCAs by interacting with the receptor for AGEs (RAGE), and ALA or PIO significantly reversed this effect. In both RSCAs and primary CSMCs, AGEs decreased Kv1.2 and Kv1.5 channel protein expression, inhibited PPAR-γ expression, increased RAGE and NOX-2 expression. Treatment with ALA or PIO partially reversed the effects of AGEs on Kv1.2/Kv1.5 expression, accompanied by elevation of PPAR-γ level and diminished oxidative stress. Conclusion AGE/RAGE axis-induced inhibition of PPAR-γ pathway and enhancement of oxidative stress may contribute to AGEs-mediated Kv channel dysfunction and coronary vasodilation in RSCAs. Our results may provide new insights into developing therapeutic strategies to manage diabetic vasculature. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China; Natural Science Foundation of Beijing (7172059)