Adipose tissue is an active endocrine and paracrine organ that may influence the development of atherosclerosis and vascular disease. In the setting of obesity, adipose tissue produces a variety of inflammatory cytokines (or adipokines) that are known to modulate key mechanisms of atherogenesis. In particular, adipose tissue located on the surface of the heart surrounding large coronary arteries (i.e. epicardial perivascular adipose tissue) has been implicated in the pathogenesis of coronary artery disease. The present review outlines our current understanding of the cellular and molecular links between perivascular adipose tissue and atherosclerosis with a focus on potential mechanisms by which epicardial perivascular adipose tissue contributes to obesity‐related coronary disease. The pathophysiology of perivascular adipose tissue in obesity and its influence on oxidative stress, inflammation, endothelial dysfunction and vascular reactivity is addressed. In addition, the contribution of specific epicardial perivascular adipose‐derived adipokines (e.g. leptin, adiponectin) to the initiation and expansion of coronary disease is also highlighted. Finally, future investigative goals are discussed with an emphasis on indentifying novel therapeutic targets and disease markers within perivascular adipose tissue. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3
The purpose of this investigation was to test the hypothesis that KV channels contribute to metabolic control of coronary blood flow and that decreases in KV channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of KV channels with 4-aminopyridine (4-AP, 0.3 mg/kg, i.v.). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of KV channels also increased aortic pressure (P < 0.01) while reducing coronary venous Po2 (P < 0.01) at a given level of myocardial oxygen consumption (MVo2). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous Po2 in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary KV current (P < 0.01) and decreased expression of KV1.5 channels in coronary arteries (P < 0.01). Together, these data demonstrate that KV channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVo2. Our findings also indicate that decreases in KV channel current and expression contribute to impaired control of coronary blood flow in the MetS.
The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K+ (KV) and Ca2+ (CaV1.2) channels play a critical role in coronary pressure-flow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM, ic) or CaV1.2 channels with diltiazem (10 μg/min, ic). 4AP significantly decreased vasodilatory responses to H2O2 (0.3–10 μM, ic) and coronary flow at CPPs = 60–140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 ± 0.11 control vs. 0.46 ± 0.06 4-AP). In contrast, inhibition of CaV1.2 channels progressively increased coronary blood flow at CPPs > 80 mmHg and substantially diminished coronary Gc to −0.20 ± 0.11 (P < 0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) KV channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of CaV1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.
We examined the acute dose-dependent effects of intracoronary glucagon-like peptide (GLP)-1 (7–36) on coronary vascular tone, cardiac contractile function and metabolism in normal and ischemic myocardium. Experiments were conducted in open chest, anesthetized dogs at coronary perfusion pressures (CPP) of 100 and 40 mmHg before and during intracoronary GLP-1 (7–36) infusion (10 pmol/L to 1 nmol/L). Isometric tension studies were also conducted in isolated coronary arteries. Cardiac and coronary expression of GLP-1 receptors (GLP-1R) was assessed by Western blot and immunohistochemical analysis. GLP-1R was present in the myocardium and the coronary vasculature. The tension of intact and endothelium-denuded coronary artery rings was unaffected by GLP-1. At normal perfusion pressure (100 mmHg), intracoronary GLP-1 (7–36) (targeting plasma concentration 10 pmol/L to 1 nmol/L) did not affect blood pressure, coronary blood flow or myocardial oxygen consumption (MVO2); however, there were modest reductions in cardiac output and stroke volume. In untreated control hearts, reducing CPP to 40 mmHg produced marked reductions in coronary blood flow (0.50 ±0.10 to 0.17 ±0.03 mL/min/g; P < 0.001) and MVO2 (27 ±2.3 to 15 ±2.7 μL O2/min/g; P < 0.001). At CPP = 40 mmHg, GLP-1 had no effect on coronary blood flow, MVO2 or regional shortening, but dose-dependently increased myocardial glucose uptake from 0.11±0.02 μmol/min/g at baseline to 0.17±0.04 μmol/min/g at 1 nmol/L GLP-1 (P < 0.001). These data indicate that acute, intracoronary administration of GLP-1 (7–36) preferentially augments glucose metabolism in ischemic myocardium, independent of effects on cardiac contractile function or coronary blood flow.
The objective of this study was to determine whether intravenous administration of glucagon‐like peptide 1 (GLP‐1) differentially affects hemodynamic and cardiometabolic responses to exercise in lean and metabolic syndrome (MetS) swine. Experiments were conducted in chronically instrumented Ossabaw swine at rest and during graded treadmill exercise with and without a 2 hr systemic infusion of GLP‐1 (7–36) at 1.5 pmol/kg/min. GLP‐1 did not affect blood pressure, heart rate, or myocardial oxygen consumption (MVO2) at rest or during exercise. In lean swine GLP‐1 increased coronary blood flow at all levels of MVO2 (P = 0.003), and also increased the slope of the relationship between myocardial glucose uptake and MVO2 (P = 0.05). These effects of GLP‐1 were absent in MetS swine. Western blotting and immunohistochemistry demonstrated no differences in expression of the GLP‐1 receptor between lean and MetS swine in coronary (P = 0.95) or cardiac (P = 0.46) tissue. In vitro studies using myocardial tissue slices revealed that GLP‐1 (1 to 5 nM) dose dependently increased p38 MAPK activity in lean (P =0.05) but not MetS (P = 0.5) swine, and did not affect PKA activity in either group. These data indicate that the impaired in‐vivo responses to GLP‐1 in MetS are not due to altered GLP‐1 receptor content or PKA activity, but may involve reduced GLP‐1 stimulation of p38 MAPK. Support: NIH HL092245 and HL092799
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