What is the clinical evidence from this study?

Study design: Other. Population: Pressure overload-induced cardiac hypertrophy (n=34). Intervention: MEKK1 deficiency vs. Wild-type (MEKK1+/+). Primary outcome: TUNEL-positive myocytes in LV myocardium at 7 days (myocytes/mm2) (p=0.02).

July 15, 2002Open Access

The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy

Key Result

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.

Structured PICO

Does MEKK1 deficiency affect pressure overload-induced cardiac hypertrophy, apoptosis, and heart failure in mice?

Population

Adult MEKK1-deficient and wild-type mice subjected to transverse aortic banding to evaluate the role of the MEKK1-JNK pathway in cardiac hypertrophy and apoptosis over 14 days.

Exposure

Transverse aortic banding (pressure overload) for up to 14 days

Comparator

Sham operation and wild-type mice subjected to transverse aortic banding

Outcome

JNK activation, cardiac hypertrophy (LV weight/body weight, myocyte cross-sectional area), apoptosis (TUNEL staining), and cardiac function (LVEDD, LVEF)surrogate

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.

Main Result

Absolute Event Rate: 1.5% vs 0.44%

p-value: p=0.02

Limitations

Animal model findings may not directly translate to human heart failure
Lung/body weight in MEKK1-/- mice subjected to aortic banding may be underestimated because data could not be obtained from animals that died before 14 days

Abstract

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.

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