Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Physiology

Background:

• Pathological cardiac hypertrophy (PCH) is linked to heart failure and arrhythmias.
• The role of L-type calcium channel (I(Ca-L)) in PCH signaling has been debated.
• Calcium (Ca(2+)) plays a crucial role in hypertrophic signaling.

Purpose of the Study:

• To investigate if sustained increases in I(Ca-L) can induce PCH.
• To elucidate the molecular mechanisms by which I(Ca-L) influences cardiac hypertrophy.
• To examine the involvement of specific calcium signaling pathways.

Main Methods:

• Utilized transgenic mouse models with varying Ca(2+) channel subunit (β2a) expression (low and high).
• Employed cultured adult feline and neonatal rat ventricular myocytes with adenovirus-mediated β2a-GFP overexpression.
• Assessed cardiac structure, function, myocyte size, and molecular markers in vivo and in vitro.
• Investigated the effects of I(Ca-L) blockade and inhibitors of key signaling molecules (calcineurin, CaMKII, SERCA).

Main Results:

• Transgenic mice with increased β2a expression exhibited PCH markers, fibrosis, and myocyte enlargement.
• Elevated I(Ca-L) correlated with a hypercontractile phenotype, increased ejection fraction, and fractional shortening.
• In vitro studies showed β2a overexpression increased myocyte volume, protein synthesis, and specific nuclear translocations.
• These hypertrophic effects were reversed by blocking I(Ca-L) and downstream signaling pathways.

Conclusions:

• Sustained increases in I(Ca-L) are sufficient to induce pathological cardiac hypertrophy.
• PCH is mediated via the calcineurin/NFAT and CaMKII/HDAC signaling cascades.
• Both cytosolic and sarcoplasmic reticulum/endoplasmic reticulum-nuclear envelope Ca(2+) pools are implicated in this process.