TNF‐α signal transduction in rat neonatal cardiac myocytes: definition of pathways generating from the TNF‐α receptor

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Abstract
Cardiomyocyte hypertrophy and apoptosis\ud have been implicated in the loss of contractile\ud function during heart failure (HF). Moreover, patients\ud with HF have been shown to exhibit increased levels of\ud tumor necrosis factor (TNF-) in the myocardium.\ud However, the multiple signal transduction pathways\ud generating from the TNF- receptor in cardiomyocytes\ud and leading preferentially to apoptosis or hypertrophy\ud are still unknown. Here we demonstrate in neonatal rat\ud cardiomyocytes that 1) TNF- induces phosphorylation\ud of AKT, activation of NF-B, and the phosphorylation\ud of JUN kinase; 2) blocking AKT activity prevents NF-B\ud activation, suggesting a role for AKT in regulating\ud NF-B function; 3) AKT and JUN are both critical for\ud the hypertrophic effects of TNF-, since dominantnegative\ud mutants of these genes are capable of inhibiting\ud TNF--induced ANF-promoter up-regulation and\ud increase in cardiomyocyte cell size, and 4) blocking\ud NF-B, AKT, or JUN alone or in combination does not\ud sensitize cardiomyocytes to the proapoptotic effects of\ud TNF-, in contrast to other cell types, suggesting a\ud cardiac-specific pathway regulating the anti-apoptotic\ud events induced by TNF-. Altogether, the data presented\ud evidence the role of AKT and JUN in TNF--\ud induced cardiomyocyte hypertrophy and apoptosi
Funding Information
  • National Institutes of Health (R01DK52825)