Type 2 angiotensin II receptor (AT2R) deficiency exacerbates cardiac senescence and fibrosis in aging mice

Cardiac aging increases susceptibility to cardiovascular diseases. Cellular senescence may be involved in the development of age-related cardiac diseases. Extensive evidence derived from both clinical and experimental studies suggests that the type 2 angiotensin II receptor (AT2R) exerts a potent cardioprotective effect; however, its potential contribution to age-related cardiac complications remains unknown. In the present study, we used AT2R knockout (AT2-KO) and wild-type mice (WT), both aged (18–21 months) and young (4–5 months), and evaluated the repercussions of cardiac aging. Old AT2-KO mice exhibited impaired systolic and diastolic cardiac function and exacerbated fibrosis accompanied by increased expression of fibrotic markers. The absence of AT2R accelerated the cardiac senescence process in old mice, evidenced by early increase in p53 and p21. In addition, aged AT2-KO mice showed increased expression of senescence-associated secretory phenotype (SASP) components, activation of cardiac NF-κB and NLRP3-inflammasome followed by increased levels of cardiac IL-1β and IL-18 compared with aged WT mice. AT2R deficiency also resulted in significant DNA damage even in young animals, and it was associated with a 5-month reduction in median lifespan (26 months for AT2R-KO versus 31 months for WT). These findings suggest potential mechanisms whereby AT2R acts as a key mediator of cardiac senescence and cardioprotection during aging.