Role of heme oxygenase in cardiomyopathy in obese Zucker fatty rats
Visceral obesity, a serious health issue is implicated in insulin resistance and altered cardiac structure and function. Elevated inflammation, increased oxidative stress, insulin resistance, excessive extracellular matrix (ECM) deposition and tissue remodeling are among the possible mechanisms linking obesity with cardiomyopathy. Since, the cytoprotective role of the heme oxygenase (HO) system is well acknowledged, the present study investigated the effects of upregulation of the HO system by HO-inducer hemin on cardiomyopathy in obese Zucker Fatty (ZF) rats. This study also investigated the mechanisms by which HO improves insulin signaling, glucose metabolism and cardiac function in this model. HO modulates adiponectin and atrial natriuretic peptide (ANP). However, the interaction of these proteins with the HO system in ZF rats is unclear. ANP and adiponectin were also measured in this study. My thesis work showed that treatment with hemin abated inflammation and oxidative stress by attenuating pro-inflammatory-M1 phenotype macrophage infiltration and suppressing cytokines/chemokines including TNF-α, IL-1β, IL-6, monocyte-chemoattractant protein-1, macrophage inhibitory protein-1α and endothelin-1. Furthermore, hemin treatment suppressed ECM/heart failure proteins such as osteopontin and osteoprotegerin, collagen IV, fibronectin and transforming growth factor-𝛽, reduced cardiac hypertrophy and cardiac lesions and enhanced ANP, adiponectin, insulin sensitivity and HO-1 concentrations. Interestingly, hemin treatment improved several compromised echocardiographic and hemodynamic parameters including left-ventricular diastolic and systolic free wall thickness, mean-arterial pressure, arterial systolic pressure, arterial diastolic pressure and cardiac output. In contrast, the HO inhibitor, stannous mesoporphyrin nullified the effects of hemin. In conclusion, my thesis data strongly suggest protective effects of hemin-induced upregulated HO system against impaired insulin signaling and cardiomyopathy in obese Zucker rats. The suppression of inflammatory/oxidative mediators, ECM and profibrotic proteins, heart failure proteins, left-ventricular hypertrophy, cardiac lesions and the concomitant increase in ANP and adiponectin levels are some of the mechanisms by which HO enhanced insulin signaling, improved glucose metabolism and cardiac tissue morphology and function in obese Zucker rats.
DegreeDoctor of Philosophy (Ph.D.)
CommitteePrasad, Kailash; Hiebert, Linda; Mulligan, Sean; Lee, Paul
Copyright DateApril 2016
Cardiomyopathy, Cardiac hemodynamics, Obesity, Inflammation, Heme oxygenase, Macrophage Infiltration, Chemokines, Cytokines