The Risk of Heart Failure and Cardiometabolic Complications in Obesity May Be Masked by an Apparent Healthy Status of Normal Blood Glucose

Abstract

Although many obese individuals are normoglycemic and asymptomatic of cardiometabolic complications, this apparent healthy state may be a misnomer. Since heart failure is a major cause of mortality in obesity, we investigated the effects of heme-oxygenase (HO) on heart failure and cardiometabolic complications in obese normoglycemic Zucker-fatty rats (ZFs). Treatment with the HO-inducer, hemin, reduced markers of heart failure, such as osteopontin and osteoprotegerin, abated left-ventricular (LV) hypertrophy/fibrosis, extracellular matrix/profibrotic proteins including collagen IV, fibronectin, TGF-β1, and reduced cardiac lesions. Furthermore, hemin suppressed inflammation by abating macrophage chemoattractant protein-1, macrophage-inflammatory protein-1 alpha, TNF-α, IL-6, and IL-1β but enhanced adiponectin, atrial-natriuretic peptide (ANP), HO activity, insulin sensitivity, and glucose metabolism. Correspondingly, hemin improved several hemodynamic/echocardiographic parameters including LV-diastolic wall thickness, LV-systolic wall thickness, mean-arterial pressure, arterial-systolic pressure, arterial-diastolic pressure, LV-developed pressure, +dP/dt, and cardiac output. Contrarily, the HO-inhibitor, stannous mesoporphyrin nullified the hemin effect, exacerbating inflammatory/oxidative insults and aggravated insulin resistance (HOMA-index). We conclude that perturbations in insulin signaling and cardiac function may be forerunners to overt hyperglycemia and heart failure in obesity. Importantly, hemin improves cardiac function by suppressing markers of heart failure, LV hypertrophy, cardiac lesions, extracellular matrix/profibrotic proteins, and inflammatory/oxidative mediators, while concomitantly enhancing the HO-adiponectin-ANP axis.

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“…Moreover, our recent findings indicate that the suppression of pericardial adiposity is associated with improved cardiac function. 35,64 Hemin also enhanced HO-1, HO activity, and the total antioxidant capacity in ZL-control rats and correspondingly reduced pericardial adiposity, 8-isoprostane, TNF-a, IL-6, IL-1b, and fasting glucose. However, the magnitude of hemin effects on ZL controls was smaller as compared to ZFs with aberrant HO-1 and HO activity.…”

Mechanisms by which heme oxygenase rescue renal dysfunction in obesity

“…Immunohistochemistry was done as we previously described [15,18,26,29] . Sections of 5 µm of whole kidney were treated with bovine serum albumin in phosphate buffered saline to avoid non-specific staining and incubated overnight with ED1 antibody (1:5 dilution, Santa Cruz Biotechnology, CA), and subsequently with goat anti-mouse IgG for 30 min (1:200 dilution; Jackson ImmunoResearch Laboratories, Inc., ME, USA).…”

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“…13 It was reported that increased levels of TNF-α in hearts from diabetic rodents is significantly correlated with development of LV dysfunction and is negatively correlated with degree of contractility. [38][39][40][41] This cytokine is also responsible for perturbations in cardiomyocyte metabolism given its negative effect on the intracellular cascade triggered by activation of insulin receptor. 32 In the current study, LASSBio-2090 normalized the upregulation of TNF-α in the heart tissue from ZDF rats with DC and this was reflected in improved LV function in vivo as depicted by the normalization of contractility and compliance and reduction in cardiac remodeling.…”