Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium

Abstract

Objective 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.

Investigating the Metabolic Syndrome

“…Altered myocardial vascular function in Ossabaw pigs fed with atherogenic diet has been linked to decreased myocardial endothelial nitric oxide (NO) synthase functionality and NO bioavailability (Bradley et al , 2015), and in Yucatan pigs to impaired function of large-conductance Ca 2+ -activated K + (BK Ca ) channels (Mokelke et al , 2005). MetS in Ossabaw pigs induced by high-cholesterol diet also impairs signaling of cardiac angiogenesis (Elmadhun et al , 2014a) thereby restricting the compensatory capacity of the myocardium for recruiting adequate blood and oxygen supplies.…”

Calcific Aortic Valve Disease: Part 2—Morphomechanical Abnormalities, Gene Reexpression, and Gender Effects on Ventricular Hypertrophy and Its Reversibility

“…Notch signaling regulates stem/progenitor cell differentiation into cardiomyocytes and interacts with other signaling pathways to improve myocardial dysfunction, in part by inducing angiogenesis to enhance myocardial perfusion with rising myocardial energy demands; inhibition of Notch signaling might underlie decreased angiogenesis [16]. By controlling the preservation and commitment of a cardiac stem cell compartment, Notch may also protect the heart from an excessive and detrimental hypertrophic response and could thus foster cardiomyocyte survival; the biological outcome of Notch action is dosage-sensitive [17].…”

Subcellular ROS Signaling in Cardiovascular Disease

“…Metabolic syndrome characterized by hypertension, obesity, glucose intolerance (diabetes), and hyperlipidemia is often accompanied by CVD. The endothelial dysfunction associated with metabolic syndrome has also been shown to have diminished angiogenic response and aberrant collateral vessels to chronic myocardial ischemia in large animal model [19,20].…”