Autophagy activation attenuates angiotensin II-induced cardiac fibrosis

• Autophagy was activated in response to Ang II stimulation in vitro and in vivo.
• Rapa suppressed Ang II-induced upregulation of ECM in rat CFs.
• CQ or ATG5 knockdown aggravated Ang II-induced upregulation of ECM in rat CFs.
• Rapa attenuated, while CQ exacerbated, Ang II-induced cardiac fibrosis in mice.

Autophagy has been involved in numerous diseases processes. However, little is known about the role of autophagy in cardiac fibrosis. Thus, whether or not angiotensin II (Ang II)-induced autophagy has a regulatory function on cardiac fibrosis was detected in vitro and in vivo. In rat cardiac fibroblasts (CFs) stimulated with Ang II, activated autophagy was observed using transmission electron microscopic analysis (TEM), immunofluorescence and Western blot. In Ang II-infused mice, increased co-localization of LC3 puncta with vimentin was observed. In rat CFs, co-treated with rapamycin (Rapa), an autophagy inducer, Ang II-induced the upregulation of type I collagen (Col-I), fibronectin (FN) was decreased. Conversely, inhibition of autophagy by chloroquine (CQ), an autophagy inhibitor, or knockdown of ATG5, a key component of the autophagy pathway by specific siRNA, aggravated Ang II-mediated the accumulation of Col-I and FN. Furthermore, in C57 BL/6 mice with Ang II infusion, intraperitoneal administration of Rapa ameliorated Ang II-induced cardiac fibrosis and cardiac dysfunction, while CQ treatment not only exacerbated Ang II-mediated cardiac fibrosis and cardiac dysfunction, but also impaired cardiac function. These findings suggest that autophagy may exert a protective role to attenuate excess extracellular matrix (ECM) accumulation in the heart.