Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-α

Abstract

Aims

Advanced heart failure is often associated with reduced myocardial fatty acid oxidation capacity. We have previously observed that failing hearts of mice with overexpression of angiotensinogen in the myocardium exhibit marked reduction of key regulatory proteins of fatty acid oxidation. In the present study, we determined whether exposure of adult rat cardiac (ARC) myocytes to angiotensin II (Ang II) influences expression of fatty acid translocase, muscle-type carnitine palmitoyl transferase-I, and medium-chain acyl-CoA dehydrogenase.

Methods and results

Ang II reduced mRNA expression of the three regulatory proteins in ARC myocytes during the entire 14-days culture period. However, protein expression and palmitate oxidation rate remained unaltered for 7 days, but subsequently markedly decreased. The decrease of protein expression and of fatty acid oxidation coincided with the onset of increased protein expression of tumour necrosis factor-α (TNF-α). The effect of Ang II was completely abolished by either blocking TNF-α formation through inhibition of reactive oxygen species-mediated activation of nuclear factor-κB or by neutralizing TNF-α with a specific antibody. Activation of peroxisome proliferator-activated receptor-α (PPARα) and PPARβ/δ counteracted Ang II-mediated reduction of the fatty acid oxidation pathway.

Conclusion

Prolonged exposure of cardiac myocytes to Ang II elicits downregulation of the fatty acid oxidation pathway mediated by enhanced synthesis of TNF-α.

Myocytes, Cell culture, Energy metabolism, Angiotensin, Remodelling