on May 8, 2009
Published online before print May 8, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.812099
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Original Article |
Control By Circulation Factors Of Mitochondrial Function And Transcription Cascade In Heart Failure: A Role For Endothelin-1 And Angiotensin-II
1 INSERM, U-769 and University of Paris-Sud, Châtenay-Malabry, France;
2 CHRU, Strasbourg, France
3 E-mail: anne.garnier{at}u-psud.fr
Background—Evidence is emerging to support the concept that the failing heart is "energy-depleted" and that defects in energy metabolism are important determinant in the development and the progression of the disease. We have previously shown that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure (CHF) is linked to decreased expression of the gene encoding transcriptional PPAR
coactivator-1alpha (PGC-1
), the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of CHF treated patients and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown.
Methods and Results—In CHF patients treated with angiotensin-converting enzyme inhibition (ACEi), cardiac oxidative capacity, measured in saponin permeabilized fibers, was 25% lower and PGC-1 protein content was 34% lower compared with non-failing controls. In a rat model of myocardial infarction, ACEi therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of PGC-1 and its transcription cascade were evaluated after a 48 hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and to a lesser degree angiotensin II (-20%) decreased PGC-1 mRNA content while other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline).
Conclusions—Taken together, these results show that despite ACEi treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin and angiotensin could be involved in the down-regulation of the mitochondrial transcription cascade.
Key Words: angiotensin • endothelin • heart failure • PGC-1alpha • mitochondrial biogenesis
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