MEKK1 deficiency in mice subjected to cardiac pressure overload did not prevent cardiac hypertrophy but resulted in significantly increased myocyte apoptosis (1.50 vs 0.44 myocytes/mm2) and higher mortality.
Does MEKK1 deficiency affect pressure overload-induced cardiac hypertrophy, apoptosis, and heart failure in mice?
MEKK1 is required for pressure overload-induced JNK activation and protects against apoptosis and heart failure, but is dispensable for the development of cardiac hypertrophy.
Absolute Event Rate: 1.5% vs 0.44%
p-value: p=0.02
Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
Sadoshima et al. (2002) studied Pressure overload-induced cardiac hypertrophy (n=34). MEKK1 deficiency vs. Wild-type (MEKK1+/+) was evaluated on TUNEL-positive myocytes in LV myocardium at 7 days (myocytes/mm2) (p=0.02). MEKK1 deficiency in mice subjected to cardiac pressure overload did not prevent cardiac hypertrophy but resulted in significantly increased myocyte apoptosis (1.50 vs 0.44 myocytes/mm2) and higher mortality.