Arrhythmogenic cardiomyopathy (AC) is a familial heart muscle disease with mutations of desmosomal gene and its pathogenesis is related with mutations of desmosomal gene and abnormality of connexin43 (Cx43). One of Rho GTPase, RhoA involves in many pathological processes and is regulated by desmosomal gene PKP2. We aim to identify if PKP2 regulate RhoA activity in myocardium of AC patients, the activity change of RhoA in patients' myocardium and to investigate the effect of active RhoA on the protein expression of Cx43 in myocardial cells. The protein expression level was assessed by western blot and the activity of RhoA was assessed by RhoA protein activation assay. Our results showed that the expression of PKP2 was decreased in myocardium of three patients, one of which carried PKP2 mutations. The activity of RhoA in myocardium was increased in myocardium of AC as compared with healthy control except for the patient with PKP2 mutation, the expression of Cx43 was also increased in those patients with increased activity of RhoA. The results in vitro demonstrated that the increase of active RhoA can cause the change of protein expression of Cx43 in HL-1 cardiomyocytes. In conclusion, regulation of RhoA activity is complex in the myocardium of AC and the activity of RhoA is increased in AC patients without PKP2 mutations. What's more, the active RhoA affects the protein expression of Cx43 in vivo and in vitro, this may be the possible disease mechanism of AC.
Keywords: Arrhythmogenic cardiomyopathy; RhoA; activity; connexin 43; cytoskeleton.