Nifedipine inhibits cardiac hypertrophy and left ventricular dysfunction in response to pressure overload

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Pharmacology

Background:

• Pathological cardiac hypertrophy is driven by protein kinase activation, leading to histone deacetylase (HDAC) phosphorylation and transcription factor desuppression.
• Nuclear factor of activated T cell (NFAT) is a key transcription factor implicated in the development of cardiac hypertrophy.
• L-type Ca(2+) channel blockers, like nifedipine, are potential modulators of these hypertrophic signaling pathways.

Purpose of the Study:

• To investigate the hypothesis that nifedipine inhibits pathological cardiac hypertrophy by blocking calcium calmodulin-dependent kinase II (CaMKII) and NFAT activation.
• To evaluate the efficacy of a subpressor dose of nifedipine in a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy.

Main Methods:

• Mice underwent sham operation or TAC for two weeks, with or without nifedipine treatment (10 mg/kg/day).
• Hemodynamic parameters, cardiac and lung weights, myocyte size, and fetal gene expression were assessed.
• Activation of CaMKII and NFAT signaling, including specific phosphorylation events and HDAC4 localization, was analyzed.

Main Results:

• Nifedipine significantly attenuated TAC-induced increases in left ventricular weight/body weight and myocyte cross-sectional area.
• Nifedipine reduced the expression of fetal-type genes (e.g., atrial natriuretic factor) and improved cardiac function (ejection fraction).
• Nifedipine inhibited TAC-induced NFAT-mediated transcription, CaMKII activation (Thr 286 phosphorylation), and phenylephrine-induced CaMKII/NFAT activation.

Conclusions:

• A subpressor dose of nifedipine effectively inhibits pathological cardiac hypertrophy in mice subjected to TAC.
• Nifedipine's cardioprotective effects are mediated by the inhibition of CaMKII and NFAT signaling pathways.
• These findings highlight a potential therapeutic role for nifedipine in managing pathological cardiac hypertrophy.