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Item Effect of coronary perivascular adipose tissue on vascular smooth muscle function in metabolic syndrome(2013-12-19) Owen, Meredith Kohr; Tune, Johnathan D.; Considine, Robert V.; March, Keith Leonard, 1963-; Sturek, Michael Stephen; Witzmann, F. A. (Frank A.)Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.Item Metabolic Syndrome Impairs Notch Signaling and Promotes Apoptosis in Chronically Ischemic Myocardium(Elsevier, 2014-09) Elmadhun, Nassrene Y.; Sabe, Ashraf A.; Lassaletta, Antonio D.; Chu, Louis M.; Kondra, Katelyn; Sturek, Michael; Sellke, Frank W.; Department of Cellular & Integrative Physiology, IU School of MedicineObjective Impaired angiogenesis is a known consequence of metabolic syndrome (MetS), however, the mechanism is not fully understood. Recent studies have shown that the Notch signaling pathway is an integral component of cardiac angiogenesis. We tested in a clinically relevant swine model the effects of MetS on Notch and apoptosis signaling in chronically ischemic myocardium. Methods Ossabaw swine were fed either a regular diet (CTL, n=8) or a high-cholesterol diet (MetS, n=8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, animals underwent cardiac harvest of the ischemic myocardium. Results There was down-regulation of pro-angiogenesis proteins Notch2, Notch4, Jagged2, Ang1 and ENOS in the MetS group compared to CTL. There was also up-regulation of pro-apoptosis protein Caspase8, and down-regulation of anti-angiogenesis protein pFOX03, and pro-survival proteins pP38 and HSP90 in the MetS group. Cell death was increased in the MetS group compared to CTL. Both CTL and MetS groups had similar arteriolar count and capillary density, and Notch3 and Jagged1 were both similarly concentrated in the smooth muscle wall in both groups. Conclusions MetS in chronic myocardial ischemia significantly impairs Notch signaling by down regulating Notch receptors, ligands and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, thus suggesting that inhibition of Notch signaling may underlie decreased angiogenesis in later stages of MetS.