title: Caloric restriction ameliorates angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy.
abstract: Angiotensin II-induced cardiac damage is associated with oxidative stress-dependent mitochondrial dysfunction. Caloric restriction (CR), a dietary regimen that increases mitochondrial activity and cellular stress resistance, could provide protection. We tested that hypothesis in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs). CR (60% of energy intake for 4 weeks) decreased mortality in dTGRs. CR ameliorated angiotensin II-induced cardiomyocyte hypertrophy, vascular inflammation, cardiac damage and fibrosis, cardiomyocyte apoptosis, and cardiac atrial natriuretic peptide mRNA overexpression. The effects were blood pressure independent and were linked to increased endoplasmic reticulum stress, autophagy, serum adiponectin level, and 5' AMP-activated protein kinase phosphorylation. CR decreased cardiac p38 phosphorylation, nitrotyrosine expression, and serum insulin-like growth factor 1 levels. Mitochondria from dTGR hearts showed clustered mitochondrial patterns, decreased numbers, and volume fractions but increased trans-sectional areas. All of these effects were reduced in CR dTGRs. Mitochondrial proteomic profiling identified 43 dTGR proteins and 42 Sprague-Dawley proteins, of which 29 proteins were in common in response to CR. We identified 7 proteins in CR dTGRs that were not found in control dTGRs. In contrast, 6 mitochondrial proteins were identified from dTGRs that were not detected in any other group. Gene ontology annotations with the Panther protein classification system revealed downregulation of cytoskeletal proteins and enzyme modulators and upregulation of oxidoreductase activity in dTGRs. CR provides powerful, blood pressure-independent, protection against angiotensin II-induced mitochondrial remodeling and cardiac hypertrophy. The findings support the notion of modulating cardiac bioenergetics to ameliorate angiotensin II-induced cardiovascular complications.
authors: Institute of Biomedicine, PO Box 63, University of Helsinki, Helsinki FI-00014, Finland.
authors: Piet
authors: P
authors: Finckenberg
authors: Ove
authors: O
authors: Eriksson
authors: Marc
authors: M
authors: Baumann
authors: Saara
authors: S
authors: Merasto
authors: Maciej M
authors: MM
authors: Lalowski
authors: Jouko
authors: J
authors: Levijoki
authors: Kristiina
authors: K
authors: Haasio
authors: Ville
authors: V
authors: Kytö
authors: Dominik N
authors: DN
authors: Muller
authors: Friedrich C
authors: FC
authors: Luft
authors: Matej
authors: M
authors: Oresic
authors: Eero
authors: E
authors: Mervaala
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D031204:Caloric Restriction / Q000379:methods*; D006332:Cardiomegaly / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020543:Proteome / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D015996:Survival Rate; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020543:Proteome; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin