Raj Kishore1, Prasanna Krishnamurthy2, Venkata Naga Srikanth Garikipati3, Cindy Benedict3, Emily Nickoloff3, Mohsin Khan3, Jennifer Johnson3, Anna M Gumpert3, Walter J Koch4, Suresh Kumar Verma5. 1. Center for Translational Medicine, Temple University, Philadelphia 19140, USA; Department of Pharmacology, Temple University, Philadelphia 19140, USA. Electronic address: raj.kishore@temple.edu. 2. Department of Cardiovascular Science, Houston Methodist Research Institute, Houston 77030, USA. 3. Center for Translational Medicine, Temple University, Philadelphia 19140, USA. 4. Center for Translational Medicine, Temple University, Philadelphia 19140, USA; Department of Pharmacology, Temple University, Philadelphia 19140, USA. 5. Center for Translational Medicine, Temple University, Philadelphia 19140, USA. Electronic address: suresh.verma@temple.edu.
Abstract
BACKGROUND: Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function. METHODS AND RESULTS: Chronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling. CONCLUSION: Our data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.
BACKGROUND: Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function. METHODS AND RESULTS: Chronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling. CONCLUSION: Our data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.
Authors: Suresh K Verma; Hind Lal; Honey B Golden; Fnu Gerilechaogetu; Manuela Smith; Rakeshwar S Guleria; Donald M Foster; Guangrong Lu; David E Dostal Journal: Cardiovasc Res Date: 2010-12-03 Impact factor: 10.787
Authors: Hind Lal; Suresh K Verma; Honey B Golden; Donald M Foster; Manuela Smith; David E Dostal Journal: J Mol Cell Cardiol Date: 2008-09-26 Impact factor: 5.000
Authors: Suresh K Verma; Venkata N S Garikipati; Prasanna Krishnamurthy; Sarah M Schumacher; Laurel A Grisanti; Maria Cimini; Zhongjian Cheng; Mohsin Khan; Yujia Yue; Cindy Benedict; May M Truongcao; Joseph E Rabinowitz; David A Goukassian; Douglas Tilley; Walter J Koch; Raj Kishore Journal: Circulation Date: 2017-06-30 Impact factor: 29.690
Authors: Maria Cimini; Venkata Naga Srikanth Garikipati; Claudio de Lucia; Zhongjian Cheng; Chunlin Wang; May M Truongcao; Anna Maria Lucchese; Rajika Roy; Cindy Benedict; David A Goukassian; Walter J Koch; Raj Kishore Journal: JCI Insight Date: 2019-07-09
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312