Objective Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of eNOS by PKC-β. However, our understanding of how PVAT potentially contributes to coronary disease as a complication of obesity/metabolic syndrome (MetS) remains limited. The current study investigated whether PVAT derived leptin impairs coronary vascular function via PKC-β in MetS. Methods and Results Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw miniature swine for isometric tension studies. Endothelial-dependent vasodilation to bradykinin was significantly reduced in MetS. PVAT did not affect bradykinin-mediated dilation in arteries from lean swine, but significantly exacerbated endothelial dysfunction in arteries from MetS swine. PVAT-induced impairment was reversed by inhibition of either PKC-β with ruboxistaurin or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western and immunohistochemical analysis demonstrated increased PVAT-derived leptin and coronary leptin receptor (ObR) density with MetS. Coronary PKC-β activity was increased in both MetS arteries exposed to PVAT and lean arteries exposed to leptin. Finally, leptin-induced endothelial dysfunction was reversed by ruboxistaurin. Conclusions Increases in epicardial PVAT leptin exacerbate coronary endothelial dysfunction in MetS via a PKC-β-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.

HDM2 regulates p53 by binding to its transactivation domain and promoting its ubiquitin‐dependent degradation. Crystallographic analysis of the HDM2/p53 complex revealed that three hydrophobic residues (F19, W23, L26) along one face of the p53 helical peptide are essential for binding (see picture). Terphenyl‐based antagonists mimic the α‐helical region of p53 and disrupt HDM2/p53 complexation.

The role of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in regulation of coronary microvascular function is widely appreciated, but molecular and functional changes underlying the deleterious influence of metabolic syndrome (MetS) have not been determined. Male Ossabaw miniature swine consumed for 3-6 mo a normal diet (11% kcal from fat) or an excess-calorie atherogenic diet that induces MetS (45% kcal from fat, 2% cholesterol, 20% kcal from fructose). MetS significantly impaired coronary vasodilation to the BK(Ca) opener NS-1619 in vivo (30-100 microg) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 microM). MetS reduced whole cell penitrem A (1 microM)-sensitive K(+) current and NS-1619-activated (10 microM) current in isolated coronary vascular smooth muscle cells. MetS increased the concentration of free intracellular Ca(2+) and augmented coronary vasoconstriction to the L-type Ca(2+) channel agonist BAY K 8644 (10 pM-10 nM). BK(Ca) channel alpha and beta(1) protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BK(Ca) channel function and is accompanied by significant increases in L-type Ca(2+) channel-mediated coronary vasoconstriction.

Conducting accurate cloud microphysical measurements from airborne platforms poses a number of challenges. The technique of phase Doppler interferometry (PDI) confers numerous advantages relative to traditional light-scattering techniques for measurement of the cloud drop size distribution, and, in addition, yields drop velocity information. Here, we describe PDI for the purposes of aiding atmospheric scientists in understanding the technique fundamentals, advantages, and limitations in measuring cloud microphysical properties. The performance of the Artium Flight PDI, an instrument specifically designed for airborne cloud measurements, is studied. Drop size distributions, liquid water content, and velocity distributions are compared with those measured by other airborne instruments.

ϩ (KV) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H2O2, as responses were attenuated by the KV channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that KV channels participate in coronary reactive hyperemia and examined the role of KV channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 Ϯ 5% and inhibited hyperemic volume 32 Ϯ 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N G -nitro-L-arginine methyl ester (L-NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L-NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 Ϯ 6% block at 9 g/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 M correolide, a selective KV1 antagonist (76 Ϯ 7% and 47 Ϯ 2% block, respectively, at 1 M). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 Ϯ 6% block at 10 g/min) and by correolide in vitro (29 Ϯ 4% block at 1 M). KV current in smooth muscle cells was inhibited by 4-AP (IC50 1.1 Ϯ 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for KV1 family members was detected in coronary arteries. Our data indicate that KV channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine-and NO-induced vasodilation. ischemic vasodilation; adenosine; 4-aminopyridine; delayed rectifier potassium channel; vascular smooth muscle IN THE CORONARY CIRCULATION, a brief period of ischemia is normally followed by a large and transient compensatory increase in blood flow. This phenomenon of reactive hyperemia, different from active (also known as functional or metabolic) hyperemia, is thought to represent a repayment of blood flow debt and is attributed to the accumulation of ischemic vasodilator metabolites. Evidence supports both adenosine and nitric oxide (NO) as mediators of reactive hyperemia (2, 4, 12, 52). Importantly, however, neither block of adenosine nor NO signaling can completely abolish reactive hyperemia (56). Thus the mechanisms of reactive hyperemia remain incompletely understood. Moreover, other mediators have been suggested, and it is likely that future studies will identify additional candidates. Rather than focus on putative metabolites underlying reactive hyperemia, we have turned our attention to possible end-effectors in vascular smooth muscle. K ϩ channels are likely targets of vasodilator metabolites, because K ϩ channels determine membrane potential and thus vascular tone (27,35). Previous studies have focused on Ca 2ϩ /voltage-sensitive (BK Ca ) and ATP-dependent (K ATP ) K ϩ channels. To date, only one study suggests a role for BK C...