title: Heme oxygenase suppresses markers of heart failure and ameliorates cardiomyopathy in L-NAME-induced hypertension.
abstract: Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.
authors.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5. Electronic address: joseph.ndisang@usask.ca.
authors.forename: Joseph Fomusi
authors.initials: JF
authors.lastname: Ndisang
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
authors.forename: Rajni
authors.initials: R
authors.lastname: Chibbar
authors.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
authors.forename: Nina
authors.initials: N
authors.lastname: Lane
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000097:blood; D054405:Chemokine CCL3 / Q000097:blood; D006152:Cyclic GMP / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism*; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000975:Antioxidants; D015415:Biomarkers; D002316:Cardiotonic Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D006418:Heme; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D001120:Arginine; D015237:Dinoprost; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP; C048849:heme arginate; D019331:NG-Nitroarginine Methyl Ester
keywords: Heme oxygenase; Heme-arginate; Hypertension; Inflammation; Osteopontin; Osteoprotegerin oxidative stress