TRV027 REDUCES BLOOD PRESSURE IN SHR AND RESTORES VENTRICULAR HYPERTROPHY BY AFFECTING CONNEXIN 43 PATHWAY

Abstract

Objective: Hypertension is one of the common causes of cardiovascular diseases. Angiotensin II (AngII) plays a crucial role in hypertension and hypertension-induced cardiac hypertrophy. Whether TRV027, an AngII type 1 receptor biased agonist, could lower blood pressure and treat hypertensive cardiac hypertrophy is unknown. Design and method: Spontaneously hypertensive rats and Wistar-Kyoto rats were selected as the study subjects. Some SHRs were giving TRV027. H9c2 cells were selected as the in vitro study subjects to explore the mechanism of action of TRV027. Results: When compared to the WKY group, the SHR group displayed a pronounced increase in blood pressure. However, after giving subcutaneous pump of TRV027, blood pressure exhibited a marked reduction. Based on the Doppler ultrasound data, prior to the intervention, the SHR group had higher values for LVAWs, LVAWd, LVPWs, and LVPWd when contrasted with the WKY group. Moreover, the left ventricular mass in the SHR group also increased significantly (P<0.05). After the intervention with TRV027 in the SHR group, all the above-mentioned cardiac Doppler parameters were lower than those in the SHR group. HE staining of cardiac sections revealed a slight disarray in myocardial arrangement and significant myocardial hypertrophy in the SHR group. Compared with the WKY group, the level of Cx43 in the heart tissue of the SHR group was decreased, and the phosphorylation of MAPK and ERK2 was increased. After administration of TRV027, the expression levels of these proteins were restored. In the cell intervention, the expression level of Cx43 was significantly decreased, the phosphorylation levels of MAPK and ERK2 were increased, and the levels of MHC and ANP were increased in the AngII intervention group. After the intervention of TRV027 the expressions of Cx43 and MAPK/ERK pathways and MHC and ANP were restored. When Cx43 inhibitor was given to H9C2 cells,along with the decrease of Cx43 expression, the phosphorylation levels of MAPK and ERK2 were increased, while the levels of MHC and ANP were significantly increased. Conclusions: TRV027 lower blood pressure in SHR and ameliorate cardiac hypertrophy induced by hypertension. This effect is likely achieved through the Cx43 pathway.