Cellular FLICE-inhibitory protein protects against cardiac remodeling induced by angiotensin II in mice.
The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP(+/-) mice and transgenic mice with cardiac-specific overexpression of the human cFLIP(L) gene. Our results demonstrated that the cFLIP(+/-) mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.
Li
Hongliang
H
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, People's Republic of China. lihl@whu.edu.cn
Tang
Qi-Zhu
QZ
Liu
Chen
C
Moon
Mark
M
Chen
Manyin
M
Yan
Ling
L
Bian
Zhou-Yan
ZY
Zhang
Yan
Y
Wang
Ai-Bing
AB
Nghiem
Mai P
MP
Liu
Peter P
PP
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020257:Ventricular Remodeling
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases