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Published on: September 28, 2015
Autophagy activation attenuates angiotensin II-induced cardiac fibrosis
Shenglan Liu1, Shaorui Chen1, Min Li1
1Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
Abstract:
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.
Insights
Autophagy activation protects against cardiac fibrosis by reducing extracellular matrix accumulation. Inhibiting autophagy worsens fibrosis and cardiac dysfunction, suggesting a protective role in heart disease.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Molecular Medicine
Background:
- Autophagy is implicated in various diseases, but its role in cardiac fibrosis remains unclear.
- Cardiac fibrosis, characterized by excessive extracellular matrix deposition, contributes to heart dysfunction.
- Angiotensin II (Ang II) is a key mediator in cardiovascular remodeling and fibrosis.
Purpose of the Study:
- To investigate the regulatory role of Angiotensin II (Ang II)-induced autophagy in cardiac fibrosis.
- To determine if modulating autophagy affects Ang II-mediated extracellular matrix accumulation in vitro and in vivo.
Main Methods:
- In vitro studies using rat cardiac fibroblasts (CFs) stimulated with Ang II.
- In vivo studies using Ang II-infused C57 BL/6 mice.
- Autophagy modulation using rapamycin (inducer) and chloroquine (inhibitor), and ATG5 knockdown.
- Assessment of autophagy activation (TEM, immunofluorescence, Western blot, LC3 puncta) and fibrosis markers (Col-I, FN).
Main Results:
- Ang II activated autophagy in CFs and induced cardiac fibrosis markers in mice.
- Autophagy induction (rapamycin) reduced Ang II-induced collagen and fibronectin accumulation.
- Autophagy inhibition (chloroquine, ATG5 knockdown) exacerbated Ang II-mediated fibrosis and cardiac dysfunction.
- Rapamycin treatment ameliorated Ang II-induced cardiac fibrosis and dysfunction in mice.
- Chloroquine treatment worsened Ang II-induced cardiac fibrosis and cardiac dysfunction.
Conclusions:
- Autophagy plays a protective role in attenuating Ang II-induced cardiac fibrosis.
- Modulating autophagy can be a potential therapeutic strategy for cardiac fibrosis and dysfunction.
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