Angiotensin II as candidate of cardiac cachexia.
OBJECTIVE
Congestive heart failure is increasing in prevalence and represents a major public health problem. The syndrome of advanced heart failure often includes muscle wasting, commonly termed cardiac cachexia, which is a predictor of poor outcome. Mechanisms of cardiac cachexia are poorly understood, but there is recent evidence that increased angiotensin II, interacting with the insulin-like growth factor-1 system, plays an important role.


RESULTS
In animals, angiotensin II produces weight loss through a pressor-independent mechanism, accompanied by decreased levels of circulating and skeletal muscle insulin-like growth factor-1 and increased mRNA levels of the ubiquitin ligases atrogin-1 and Muscle RING finger-1 in skeletal muscle. Reduced insulin-like growth factor-1 action in muscle leads to increased proteolysis, through the ubiquitin-proteasome pathway, and increased apoptosis. These changes are blocked by muscle-specific expression of insulin-like growth factor-1, likely to be via the Akt/mTOR/p70S6K signaling pathway.


CONCLUSIONS
The link between insulin-like growth factor-1, the ubiquitin-proteasome pathway, and angiotensin II effects has widespread clinical implications for the understanding of mechanisms of catabolic conditions. Therapeutic interventions targeting cross-talk mechanisms between angiotensin II and insulin-like growth factor-1 effects could provide new approaches for the treatment of muscle wasting.
Delafontaine
Patrice
P
Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. pdelafon@tulane.edu
Akao
Makoto
M
D000804:Angiotensin II / Q000494:pharmacology*; D002100:Cachexia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*
D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I