Metabolomics in angiotensin II-induced cardiac hypertrophy.
Angiotensin II (Ang II) induces mitochondrial dysfunction. We tested whether Ang II alters the "metabolomic" profile. We harvested hearts from 8-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGRs) and controls (Sprague-Dawley), all with or without Ang II type 1 receptor (valsartan) blockade. We used gas chromatography coupled with time-of-flight mass spectrometry to detect 247 intermediary metabolites. We used a partial least-squares discriminate analysis and identified 112 metabolites that differed significantly after corrections (false discovery rate q <0.05). We found great differences in the use of fatty acids as an energy source, namely, decreased levels of octanoic, oleic, and linoleic acids in dTGR (all P<0.01). The increase in cardiac hypoxanthine levels in dTGRs suggested an increase in purine degradation, whereas other changes supported an increased ketogenic amino acid tyrosine level, causing energy production failure. The metabolomic profile of valsartan-treated dTGRs more closely resembled Sprague-Dawley rats than untreated dTGRs. Mitochondrial respiratory chain activity of cytochrome C oxidase was decreased in dTGRs, whereas complex I and complex II were unaltered. Mitochondria from dTGR hearts showed morphological alterations suggesting increased mitochondrial fusion. Cardiac expression of the redox-sensitive and the cardioprotective metabolic sensor sirtuin 1 was increased in dTGRs. Interestingly, valsartan changed the level of 33 metabolites and induced mitochondrial biogenesis in Sprague-Dawley rats. Thus, distinct patterns of cardiac substrate use in Ang II-induced cardiac hypertrophy are associated with mitochondrial dysfunction. The finding underscores the importance of Ang II in the regulation of mitochondrial biogenesis and cardiac metabolomics, even in healthy hearts.
Mervaala
Eero
E
Institute of Biomedicine, University of Helsinki, Helsinki, Finland. eero.mervaala@helsinki.fi
Biala
Agnieszka
A
Merasto
Saara
S
Lempiäinen
Juha
J
Mattila
Ismo
I
Martonen
Essi
E
Eriksson
Ove
O
Louhelainen
Marjut
M
Finckenberg
Piet
P
Kaheinen
Petri
P
Muller
Dominik N
DN
Luft
Friedrich C
FC
Lapatto
Risto
R
Oresic
Matej
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000032:analysis; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods; D008929:Mitochondria, Heart / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D056564:Sirtuin 1 / Q000378:metabolism*; D015996:Survival Rate; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D015415:Biomarkers; D005227:Fatty Acids; D008041:Linoleic Acids; D013777:Tetrazoles; D000804:Angiotensin II; D019271:Hypoxanthine; D000068756:Valsartan; D056564:Sirtuin 1; D014633:Valine