title: Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice.
abstract: Sustained elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) reprograms cardiovascular cell fate, leading to cellular hypertrophy via Ca(2+)-calmodulin/calcineurin (Cn)/NFAT activation. Accumulating evidence suggests that transient receptor potential canonical (Trpc) channels play important roles in the development of pathologic cardiac hypertrophy. Here, we demonstrated that Trpc3 mediates pathologic cardiac hypertrophy in neurohumoral elevation via direct regulation of CaV1.2 expressions. Elevated PE (phenylephrine) was maintained in mice by continuous infusion using an osmotic pump. Wild-type (WT) mice, but not Trpc3 (-/-) showed a sudden decrease in blood pressure (BP) or death following elevation of BP under conditions of elevated PE. Trpc3 (-/-) mesenteric artery showed decreased PE-stimulated vasoconstriction. Analysis of morphology, function, and pathologic marker expression revealed that PE elevation caused pathologic cardiac hypertrophy in WT mice, which was prevented by deletion of Trpc3. Interestingly, protection by Trpc3 deletion seemed to be a result of reduced cardiac CaV1.2 expressions. Basal and PE induced increased expression of protein and mRNA of CaV1.2 was decreased in Trpc3 (-/-) heart. Accordingly, altered expression of CaV1.2 was observed by knockdown or stimulation of Trpc3 in cardiomyocytes. These findings suggest that Trpc3 is a mediator of pathologic cardiac hypertrophy not only through mediating part of the Ca(2+) influx, but also through control of CaV1.2 expressions.
authors: Department of Pharmacology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Jung Woo
authors: JW
authors: Han
authors: Department of Physiology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
authors: Young Ho
authors: YH
authors: Lee
authors: Department of Physiology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, South Korea.
authors: Su-In
authors: SI
authors: Yoen
authors: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA.
authors: Joel
authors: J
authors: Abramowitz
authors: Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA.
authors: Lutz
authors: L
authors: Birnbaumer
authors: Department of Pharmacology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea.
authors: Min Goo
authors: MG
authors: Lee
authors: Department of Pharmacology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea. jooyoungkim@yuhs.ac.
authors: Joo Young
authors: JY
authors: Kim
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010656:Phenylephrine / Q000378:metabolism; D050052:TRPC Cation Channels / Q000172:deficiency*; D014661:Vasoconstriction / Q000235:genetics
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D010656:Phenylephrine
keywords: Ca2+ influx; L-type Ca2+ channel; Pathologic cardiac hypertrophy; Transient receptor potential canonical channels 3