The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy
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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.
Why the study?
Does MEKK1 deficiency affect pressure overload-induced cardiac hypertrophy, apoptosis, and heart failure in mice?
Population
Adult mice deficient in MEKK1 (Mekk1-/-) and wild-type controls (Mekk1+/+ or C57BL/6)
Comparison
Transverse aortic banding for up to 14 days vs Sham operation and wild-type mice subjected to…
Design
Preclinical
Follow-up
14 days
Authors
Discussion
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Implication
MEKK1 may protect against apoptosis and mortality in pressure overload without affecting hypertrophy; hypothesis-generating for its therapeutic targeting in human HF.
Structured PICO
Does MEKK1 deficiency affect pressure overload-induced cardiac hypertrophy, apoptosis, and heart failure in mice?
P
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.
E
Exposure
Transverse aortic banding (pressure overload) for up to 14 days
C
Comparator
Sham operation and wild-type mice subjected to transverse aortic banding
O
Outcome
JNK activation, cardiac hypertrophy (LV weight/body weight, myocyte cross-sectional area), apoptosis (TUNEL staining), and cardiac function (LVEDD, LVEF)surrogate
Main Result
Absolute Event Rate: 1.5% vs 0.44%
p-value: p=0.02
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.
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
Cite This Study
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.
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