Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling

Abstract

Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signalregulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK ؊/؊ ) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK ؊/؊ hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK ؊/؊ had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK ؊/؊ compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK ؊/؊ cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Increased pAKT was maintained in hearts of diabetic caPI3K-Tg mice, and AKT was previously shown to directly inhibit apoptosis signal-regulating kinase 1 (ASK1) in response to oxidative stress [43]. Further, AKT1 or deficiency of ASK1 protects the heart against cardiac pathology [44][45][46]. Thus, PI3K (p110α) is likely to mediate protection, in part, by activation of AKT.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…4). RAF1 inhibits two pro-apoptotic kinases, apoptosis signal-regulating kinase 1 (ASK1) and mammalian sterile 20 kinase 2 (MST2), both of which have central roles in oxidant stress-induced injury [73][74][75][76] . Intriguingly, however, neither of these effects requires RAF1 kinase activity, and both are mediated by inhibitory protein-protein interactions.…”

MAP3Ks as central regulators of cell fate during development

“…This increased apoptosis results in cardiac muscle enlargement and fibrosis with subsequent left ventricular dysfunction (Yamaguchi et al, 2004). C-Raf CKO mice also display an increase in the activity of MEKK5 (ASK1), which has been shown to play an important role in the induction of neuronal and cardiac apoptosis (Kanamoto et al, 2000;Yamaguchi et al, 2003). Ablation of MEKK5 in C-Raf CKO mice rescues the enhanced-apoptosis phenotype, which suggests that C-Raf promotes cell survival in the heart through modulation of MEKK5 activity.…”

“…MEKK5-knockout mice do not exhibit developmental defects (Yamaguchi et al, 2003). However, MEKK5 is implicated in left ventricular remodeling by inducing apoptosis after myocardial infarcts (Yamaguchi et al, 2003).…”

“…However, MEKK5 is implicated in left ventricular remodeling by inducing apoptosis after myocardial infarcts (Yamaguchi et al, 2003). The loss of MEKK5 in C-Raf-deficient hearts rescues the cardiac phenotype, characterized by increased apoptosis and dilation of the heart (Yamaguchi et al, 2003). MEKK5 activates the p38 and JNK pathways (Fig.…”