BACKGROUND: Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun N-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. METHODS AND RESULTS: We investigated Mixed Lineage Kinase 3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process has not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3(-/-)) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3-/- mice subjected to chronic LV pressure overload (TAC, four weeks) developed worsened cardiac dysfunction and increased LV chamber size compared to MLK3(+/+) littermates (n=8). LV mass, pathological markers of hypertrophy (Nppa, Nppb), and cardiomyocyte size were elevated in MLK3(-/-) TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3(-/-) TAC hearts. In adult rat cardiomyocytes pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. CONCLUSIONS: These data demonstrate MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF.

OBJECTIVE: To examine the effect of hormone replacement therapy on life expectancy in postmenopausal women with different risk profiles for heart disease, breast cancer, and hip fracture. DESIGN: Decision analysis using a Markov model. Published regression models were used to link risk factors to disease incidence and to estimate the lifetime risks of developing coronary heart disease (CHD), breast cancer, hip fracture, and endometrial cancer. The impact of hormone therapy on disease incidence was estimated from published epidemiologic studies. SETTING: Mathematical model applicable to primary care. INTERVENTIONS: Treatment with hormone replacement therapy or no hormone replacement therapy. MAIN OUTCOME MEASURE: Life expectancy. RESULTS: Hormone replacement therapy should increase life expectancy for nearly all postmenopausal women, with some gains exceeding 3 years, depending mainly on an individual's risk factors for CHD and breast cancer. For women with at least 1 risk factor for CHD, hormone therapy should extend life expectancy, even for women having first-degree relatives with breast cancer. Women without any risk factors for CHD or hip fracture, but who have 2 first-degree relatives with breast cancer, however, should not receive hormone therapy. CONCLUSIONS: The benefit of hormone replacement therapy in reducing the likelihood of developing CHD appears to outweigh the risk of breast cancer for nearly all women in whom this treatment might be considered. Our analysis supports the broader use of hormone replacement therapy.