The Angiotensin Ii Type 1 Receptor-Biased Agonist Restores Ventricular Hypertrophy by Affecting the Connexin 43 Pathway in Spontaneously Hypertensive Rats

Objective: Ventricular hypertrophy, especially that caused by hypertension, is an important pathophysiological process leading to a decline in cardiac function. Reversing ventricular hypertrophy is of great significance in preventing a decline in cardiac function. Angiotensin II (AngII) plays a crucial role in hypertension-induced cardiac hypertrophy. Reportedly, TRV027, an AngII type 1 receptor (AT1R) biased agonist, can competitively bind to AT1R and inhibit the AngII-induced damage. Whether TRV027 could treat hypertensive cardiac hypertrophy remains unknown.Design and method: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were selected, and some of the SHRs were administered with TRV027. H9C2 cells were utilized for in vitro study to explore the underlying mechanism of TRV027. A multidisciplinary approach combining pathology and molecular techniques was used to explore the role and mechanism of TRV027 in restoring ventricular hypertrophy. Results: Our studies revealed that TRV027 restored hypertension-induced ventricular hypertrophy in SHRs. Moreover, the modulated expression of Connexin43 (Cx43) and phosphorylation of the p38 MAPK and ERK pathway were normalized by TRV027 in the heart tissue and H9C2 cells. After the inhibition of Cx43 expression, cardiomyocytes recovered from hypertrophy and damage, followed by the modulation of phosphorylation of the p38 MAPK and ERK pathway. Conclusions: TRV027 demonstrates a potential to lower the blood pressure in SHRs and ameliorate hypertension-induced cardiac hypertrophy. While AngII stimulated cardiomyocyte injury by decreasing Cx43 expression and increasing the phosphorylation of the MAPK and ERK pathway, TRV027 repaired the hypertrophy by restoring the expression of the Cx43 and p38 MAPK and ERK pathway.