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Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological
1Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Insights
Increases in intracellular calcium (Ca2+) drive cardiac hypertrophy. This study shows L-type Ca2+ channels are the primary source of Ca2+ activating calcineurin-NFAT signaling, leading to myocyte hypertrophy.
Area of Science:
- Cardiovascular Physiology
- Cell Biology
- Molecular Cardiology
Background:
- Cardiovascular diseases like hypertension necessitate increased myocyte force, requiring elevated intracellular calcium ([Ca2+]).
- Elevated [Ca2+] is a known signal for activating hypertrophic genes, but its source in cardiac hypertrophy remains unclear.
- Understanding the source of hypertrophic [Ca2+] is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Ca2+ influx through L-type Ca2+ channels (LTCC), T-type Ca2+ channels (TTCC), and transient receptor potential (TRP) channels in activating calcineurin (Cn)-NFAT signaling.
- To determine the primary source of Ca2+ responsible for myocyte hypertrophy.
- To elucidate the signaling pathways linking Ca2+ channels to hypertrophic gene activation.
Main Methods:
- Utilized neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs).
- Employed adenovirus-mediated gene transfer to express NFAT-GFP for monitoring nuclear translocation.
- Applied channel antagonists (Nifedipine for LTCC, SKF-96365 for TRP, Nickel for TTCC) and pacing to assess Ca2+ influx and signaling.
- Measured Ca2+ transients and LTCC currents.
Main Results:
- High extracellular Ca2+ or pacing induced NFAT nuclear translocation, which was blocked by calcineurin inhibitors.
- Nifedipine (LTCC antagonist) effectively blocked high Ca2+-induced NFAT translocation in NRVMs, while TRP and TTCC antagonists were less effective.
- TRP channel activation also led to myocyte hypertrophy, but this effect was primarily mediated through Ca2+ influx via LTCCs.
Conclusions:
- Ca2+ influx through L-type Ca2+ channels (LTCCs) is the principal source of Ca2+ that activates calcineurin-NFAT signaling in both NRVMs and AFVMs.
- While TRP channels contribute to myocyte hypertrophy, their effects appear to be dependent on concomitant Ca2+ entry through LTCCs.
- Targeting LTCCs may be a key strategy for managing cardiac hypertrophy associated with cardiovascular diseases.
Abstract:
Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs.
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