Roles of transient receptor potential channel 6 in glucose-induced cardiomyocyte injury

Abstract

BACKGROUND Diabetic cardiomyopathy (DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6 (TRPC6) protein is a very important selective calcium channel that is closely related to the development of various cardiomyopathies. AIM To explore whether TRPC6 affects cardiomyocyte apoptosis and proliferation inhibition in DCM. METHODS We compared cardiac function and myocardial pathological changes in wild-type mice and mice injected with streptozotocin (STZ), in addition to comparing the expression of TRPC6 and P-calmodulin-dependent protein kinase II (P-CaMKII) in them. At the same time, we treated H9C2 cardiomyocytes with high glucose and then evaluated the effects of addition of SAR, a TRPC6 inhibitor, and KN-93, a CaMKII inhibitor, to such H9C2 cells in a high-glucose environment. RESULTS We found that STZ-treated mice had DCM, decreased cardiac function, necrotic cardiomyocytes, and limited proliferation. Western blot and immunofluorescence were used to detect the expression levels of various appropriate proteins in the myocardial tissue of mice and H9C2 cells. Compared to those in the control group, the expression levels of the apoptosis-related proteins cleaved caspase 3 and Bax were significantly higher in the experimental group, while the expression of the proliferation-related proteins proliferating cell nuclear antigen (PCNA) and CyclinD1 was significantly lower. In vivo and in vitro , the expression of TRPC6 and P-CaMKII increased in a high-glucose environment. However, addition of inhibitors to H9C2 cells in a high-glucose environment resulted in alleviation of both apoptosis and proliferation inhibition. CONCLUSION The inhibition of apoptosis and proliferation of cardiomyocytes in a high-glucose environment may be closely related to activation of the TRPC6/P-CaMKII pathway.

Differential changes in cyclic adenosine 3′‐5′ monophosphate (cAMP) effectors and major Ca2+ handling proteins during diabetic cardiomyopathy

“…Interestingly, 12 weeks after STZ injection, DCM was associated with increases in CaMKII protein levels and CaMKII‐dependent phosphorylation of PLB. The rate of PLB phosphorylation may be the result of a balance between an upregulation in the kinase activity, which has been reported in DCM through phosphorylation, oxidation and O‐GlcNAcylation in diabetic hearts from rodents and human patients 57–60 and changes in phosphatases activity 61,62 …”