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Updated: May 12, 2026
Transverse Aortic Constriction in Mice
Published on: April 22, 2010
alpha1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice
Hiroyuki Nakayama1, Ilona Bodi, Robert N Correll
1Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract:
In noncontractile cells, increases in intracellular Ca2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca2+-dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca2+ serves as a second messenger given the high Ca2+ concentrations that control contraction. T-type Ca2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of alpha1G, which generates Cav3.1 current, to investigate whether this type of Ca2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, alpha1G transgenic mice showed no cardiac pathology despite large increases in Ca2+ influx, and they were even partially resistant to pressure overload-, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, alpha1G-/- mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in alpha1G-/- mice was rescued with the alpha1G transgene, demonstrating a myocyte-autonomous requirement of alpha1G for protection. Mechanistically, alpha1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in alpha1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of alpha1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3-/- background. Thus, cardiac alpha1G reexpression and its associated pool of T-type Ca2+ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.
Insights
T-type calcium channels (alpha1G) protect the heart from hypertrophy. In transgenic mice, alpha1G expression prevented cardiac enlargement, while its absence worsened it, revealing a protective role in cardiac health.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Ion Channel Physiology
Background:
- Intracellular calcium (Ca2+) acts as a second messenger in noncontractile cells, regulating vital processes.
- The role of Ca2+ as a second messenger in cardiomyocytes is complex due to high contraction-controlling Ca2+ levels.
- T-type Ca2+ channels, specifically alpha1G (Cav3.1), are reexpressed in adult ventricular myocytes during pathological hypertrophy, but their function is unknown.
Purpose of the Study:
- To investigate the role of cardiac alpha1G T-type Ca2+ channels in regulating the cardiac hypertrophic response.
- To determine if alpha1G-generated Ca2+ influx influences pathological cardiac remodeling.
Main Methods:
- Generation of cardiac-specific transgenic mice with inducible alpha1G expression.
- Utilized pressure overload, isoproterenol, and exercise models to induce cardiac hypertrophy.
- Investigated the interaction between alpha1G and NOS3 (nitric oxide synthase 3) and its downstream effects on cGMP-dependent protein kinase type I activity.
- Employed genetic knockout (alpha1G-/- and Nos3-/-) and pharmacological inhibition of NOS3.
Main Results:
- Unexpectedly, alpha1G transgenic mice showed no cardiac pathology and were resistant to various hypertrophy-inducing stimuli.
- alpha1G-/- mice exhibited exacerbated hypertrophic responses to pressure overload and isoproterenol, which was rescued by the alpha1G transgene.
- Mechanistically, alpha1G interacted with NOS3, enhancing cGMP-dependent protein kinase type I activity in response to pressure overload.
- The anti-hypertrophic effect of alpha1G was dependent on NOS3 activity, as demonstrated by inhibitor studies and Nos3-/- background.
Conclusions:
- Cardiac alpha1G T-type Ca2+ channels antagonize cardiac hypertrophy.
- This protective mechanism involves a signaling pathway dependent on NOS3 and cGMP-dependent protein kinase type I.
- Reexpression of alpha1G in cardiomyocytes plays a crucial, myocyte-autonomous role in preventing pathological cardiac hypertrophy.
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