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: Joseph Fomusi Ndisang, Rajni Chibbar, Nina Lane
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 734 Pg. 23-34 (Jul 05 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24726875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Adiponectin
• Antioxidants
• Biomarkers
• Cardiotonic Agents
• Ccl2 protein, rat
• Chemokine CCL2
• Chemokine CCL3
• Endothelin-1
• Extracellular Matrix Proteins
• Interleukin-1beta
• Interleukin-6
• Tumor Necrosis Factor-alpha
• 8-epi-prostaglandin F2alpha
• 3-nitrotyrosine
• Tyrosine
• Heme
• Aldosterone
• Atrial Natriuretic Factor
• Arginine
• Dinoprost
• Heme Oxygenase (Decyclizing)
• Cyclic GMP
• heme arginate
• NG-Nitroarginine Methyl Ester

Topics

• Adiponectin (metabolism)
• Aldosterone (metabolism)
• Animals
• Antioxidants (metabolism)
• Arginine (pharmacology)
• Atrial Natriuretic Factor (metabolism)
• Biomarkers (metabolism)
• Blood Pressure (drug effects)
• Cardiomyopathies (blood, metabolism, pathology)
• Cardiotonic Agents (metabolism)
• Chemokine CCL2 (blood)
• Chemokine CCL3 (blood)
• Cyclic GMP (metabolism)
• Dinoprost (analogs & derivatives, metabolism)
• Endothelin-1 (metabolism)
• Enzyme Induction (drug effects)
• Extracellular Matrix Proteins (metabolism)
• Heart Failure (metabolism)
• Heme (pharmacology)
• Heme Oxygenase (Decyclizing) (biosynthesis, metabolism)
• Hypertension (blood, chemically induced, metabolism)
• Interleukin-1beta (blood)
• Interleukin-6 (blood)
• Male
• NG-Nitroarginine Methyl Ester (adverse effects)
• Rats
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (blood)
• Tyrosine (analogs & derivatives, metabolism)