title: Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes.
abstract: There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Biala
authors.forename: Eveliina
authors.initials: E
authors.lastname: Tauriainen
authors.forename: Antti
authors.initials: A
authors.lastname: Siltanen
authors.forename: Jin
authors.initials: J
authors.lastname: Shi
authors.forename: Saara
authors.initials: S
authors.lastname: Merasto
authors.forename: Marjut
authors.initials: M
authors.lastname: Louhelainen
authors.forename: Essi
authors.initials: E
authors.lastname: Martonen
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005796:Genes / Q000187:drug effects; D006321:Heart / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes
chemical_list: D013267:Stilbenes; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D000077185:Resveratrol