TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy

Area of Science:

• Cardiology
• Molecular Biology
• Cell Signaling

Background:

• Cardiac hypertrophy is a precursor to heart failure, often driven by neurohumoral factors like angiotensin II and endothelin-1.
• These factors activate calcineurin/NFAT pathways in cardiomyocytes via TRPC3/6 channels, leading to hypertrophic growth.
• Adenosine triphosphate (ATP), a potent calcium-mobilizing agent, does not typically induce cardiomyocyte hypertrophy.

Purpose of the Study:

• To investigate the mechanism by which ATP prevents cardiac hypertrophy.
• To elucidate the role of nitric oxide (NO) in ATP's effect on cardiomyocyte signaling.
• To identify the specific ion channels involved in ATP-mediated signaling and its anti-hypertrophic effects.

Main Methods:

• Utilized neonatal rat cardiomyocytes (NRCMs) for experimental models.
• Employed pharmacological inhibitors for nitric oxide synthase (NOS) and TRPC channels (TRPC5, TRPC6).
• Assessed NFAT activity, protein synthesis, brain natriuretic peptide (BNP) transcriptional activity, NO production, and protein kinase G (PKG) activity.

Main Results:

• ATP-induced nitric oxide (NO) production was found to negatively regulate hypertrophic signaling.
• Inhibition of NOS potentiated ATP-induced NFAT activity, protein synthesis, and BNP transcription.
• ATP increased NO production and PKG activity more than angiotensin II or endothelin-1, with TRPC5 channels mediating ATP-induced NO-cGMP-PKG signaling.

Conclusions:

• The NO-cGMP-PKG axis, activated by ATP via IP3-mediated TRPC5 channels, negatively regulates TRPC3/6-dependent hypertrophic signaling.
• This pathway explains why ATP, unlike other hypertrophic stimuli, does not induce cardiomyocyte hypertrophy.
• Targeting the NO-cGMP-PKG pathway offers a potential strategy for preventing cardiac hypertrophy.