Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure.
Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.
From the Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hanover, Germany.
Daniela
D
Fraccarollo
From the Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hanover, Germany.
Paolo
P
Galuppo
From the Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hanover, Germany.
Jonas
J
Neuser
From the Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hanover, Germany.
Johann
J
Bauersachs
From the Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hanover, Germany. widder.julian@mh-hannover.de.
Julian D
JD
Widder
D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D000099156:Superoxide Dismutase 2
D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010417:Pentaerythritol Tetranitrate; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D013481:Superoxides; D014665:Vasodilator Agents; D000099156:Superoxide Dismutase 2
fibrosis; heart failure; nitric oxide; pentaerythritol tetranitrate; rats; reactive oxygen species