Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy

Eero Mervaala, Agnieszka Biala, Saara Merasto, Juha Lempiäinen, Ismo Mattila, Essi Martonen, Ove Eriksson, Marjut Louhelainen, Piet Finckenberg, Petri Kaheinen, Dominik N. Muller, Friedrich C. Luft, Risto Lapatto, Matej Orešič

Research output: Contribution to journalArticleScientificpeer-review

29 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)508-515
JournalHypertension
Volume55
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

Fingerprint

Valsartan
Metabolomics
Cardiomegaly
Angiotensin II
Organelle Biogenesis
Sprague Dawley Rats
Sirtuin 1
Caprylates
Mitochondrial Dynamics
Transgenic Rats
Heart Mitochondria
Angiotensinogen
Angiotensin Type 1 Receptor
Hypoxanthine
Electron Transport Complex IV
Electron Transport
Renin
Gas Chromatography
Oxidation-Reduction
Tyrosine

Keywords

  • hypertrophy
  • metabolomics
  • angiotensin II
  • hypertension
  • oxidative stress

Cite this

Mervaala, E., Biala, A., Merasto, S., Lempiäinen, J., Mattila, I., Martonen, E., ... Orešič, M. (2010). Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy. Hypertension, 55, 508-515. https://doi.org/10.1161/HYPERTENSIONAHA.109.145490
Mervaala, Eero ; Biala, Agnieszka ; Merasto, Saara ; Lempiäinen, Juha ; Mattila, Ismo ; Martonen, Essi ; Eriksson, Ove ; Louhelainen, Marjut ; Finckenberg, Piet ; Kaheinen, Petri ; Muller, Dominik N. ; Luft, Friedrich C. ; Lapatto, Risto ; Orešič, Matej. / Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy. In: Hypertension. 2010 ; Vol. 55. pp. 508-515.
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Mervaala, E, Biala, A, Merasto, S, Lempiäinen, J, Mattila, I, Martonen, E, Eriksson, O, Louhelainen, M, Finckenberg, P, Kaheinen, P, Muller, DN, Luft, FC, Lapatto, R & Orešič, M 2010, 'Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy', Hypertension, vol. 55, pp. 508-515. https://doi.org/10.1161/HYPERTENSIONAHA.109.145490

Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy. / Mervaala, Eero; Biala, Agnieszka; Merasto, Saara; Lempiäinen, Juha; Mattila, Ismo; Martonen, Essi; Eriksson, Ove; Louhelainen, Marjut; Finckenberg, Piet; Kaheinen, Petri; Muller, Dominik N.; Luft, Friedrich C.; Lapatto, Risto; Orešič, Matej.

In: Hypertension, Vol. 55, 2010, p. 508-515.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy

AU - Mervaala, Eero

AU - Biala, Agnieszka

AU - Merasto, Saara

AU - Lempiäinen, Juha

AU - Mattila, Ismo

AU - Martonen, Essi

AU - Eriksson, Ove

AU - Louhelainen, Marjut

AU - Finckenberg, Piet

AU - Kaheinen, Petri

AU - Muller, Dominik N.

AU - Luft, Friedrich C.

AU - Lapatto, Risto

AU - Orešič, Matej

PY - 2010

Y1 - 2010

N2 - 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.

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KW - hypertrophy

KW - metabolomics

KW - angiotensin II

KW - hypertension

KW - oxidative stress

U2 - 10.1161/HYPERTENSIONAHA.109.145490

DO - 10.1161/HYPERTENSIONAHA.109.145490

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JF - Hypertension

SN - 0194-911X

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Mervaala E, Biala A, Merasto S, Lempiäinen J, Mattila I, Martonen E et al. Metabolomics in Angiotensin II-Induced Cardiac Hypertrophy. Hypertension. 2010;55:508-515. https://doi.org/10.1161/HYPERTENSIONAHA.109.145490