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.