TY - JOUR
T1 - Control by circulating factors of mitochondrial function and transcription cascade in heart failure
AU - Garnier, Anne
AU - Zoll, Joffrey
AU - Fortin, Dominique
AU - N'Guessan, Benoit
AU - Lefebvre, Florence
AU - Geny, Bernard
AU - Mettauer, Bertrand
AU - Veksler, Vladimir
AU - Clapier, Renee Ventura
PY - 2009/7
Y1 - 2009/7
N2 - Background-Evidence is emerging to support the concept that the fng heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-y coactivator-1a, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophys-iological mechanisms of mitochondrial dysfunction are still largely unknown. Methods and Results-In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-y coactivator-1a protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-y coactivator-1a 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 proliferator-activated receptor-y coactivator-1a mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline). Conclusions-Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.
AB - Background-Evidence is emerging to support the concept that the fng heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-y coactivator-1a, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophys-iological mechanisms of mitochondrial dysfunction are still largely unknown. Methods and Results-In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-y coactivator-1a protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-y coactivator-1a 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 proliferator-activated receptor-y coactivator-1a mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline). Conclusions-Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.
KW - Angiotensin II
KW - Endothelin-1
KW - Heart failure
KW - Mitochondrial biogenesis
KW - Proliferator-activated receptor-γ coactivator-1α
UR - http://www.scopus.com/inward/record.url?scp=77952430578&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.108.812099
DO - 10.1161/CIRCHEARTFAILURE.108.812099
M3 - Article
C2 - 19808358
AN - SCOPUS:77952430578
SN - 1941-3289
VL - 2
SP - 342
EP - 350
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
IS - 4
ER -