title: alpha1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice.
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.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Ilona
authors.initials: I
authors.lastname: Bodi
authors.forename: Robert N
authors.initials: RN
authors.lastname: Correll
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Lorenz
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C498197:Cacna1g protein, mouse; D020747:Calcium Channels, T-Type; D011994:Recombinant Proteins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse