The risk of heart failure and cardiometabolic complications in obesity may be masked by an apparent healthy status of normal blood glucose.
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.
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Shuchita
S
Tiwari
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Manish
M
Mishra
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Ashok
A
Jadhav
Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, Canada S7N 5E5.
Courtney
C
Gerger
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Paul
P
Lee
Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, Canada S7N 5E5.
Lynn
L
Weber
Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Joseph Fomusi
JF
Ndisang
D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006333:Heart Failure / Q000150:complications* / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008665:Metalloporphyrins / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography; D015854:Up-Regulation / Q000187:drug effects
D052242:Adiponectin; D001786:Blood Glucose; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019332:Endothelin-1; D007328:Insulin; D019402:Macrophage Inflammatory Proteins; D008665:Metalloporphyrins; D014409:Tumor Necrosis Factor-alpha; C055421:tin mesoporphyrin; C075750:8-epi-prostaglandin F2alpha; D006427:Hemin; D009320:Atrial Natriuretic Factor; D015237:Dinoprost; D006419:Heme Oxygenase (Decyclizing)