Murine cardiac growth, TRPC channels, and cGMP kinase I

Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), trpc6−/−, trpc3−/−, trpc3−/−/6−/−, βRM mice, and trpc3−/−/6−/− × βRM mice. βRM mice express cGKIβ only in the smooth muscle on a cGKI−/− background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, trpc6−/−, trpc3−/−, trpc3−/−/6−/−, βRM, and trpc3−/−/6−/− × βRM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3−/− mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and trpc6−/−, minimal or absent in trpc3−/−, moderate in βRM, and dramatic in trpc3−/−/6−/− βRM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in βRM mice on a TRPC3/6 × cGKI−/−KO background, indicating an “additive” coupling between both signaling pathways.Fil: Domes, Katrin. Universitat Technical Zu Munich; AlemaniaFil: Patrucco, Enrico. Universitat Technical Zu Munich; AlemaniaFil: Loga, Florian. Universitat Technical Zu Munich; AlemaniaFil: Dietrich, Alexander. Ludwig Maximilians Universitat; AlemaniaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences; Estados UnidosFil: Wegener, Jörg W.. Universitat Technical Zu Munich; AlemaniaFil: Hofmann, Franz. Universitat Technical Zu Munich; Alemani