PMID- 32029708 OWN - NLM STAT- MEDLINE DCOM- 20210309 LR - 20221207 IS - 2041-4889 (Electronic) VI - 11 IP - 2 DP - 2020 Feb 6 TI - A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKalpha. PG - 96 LID - 10.1038/s41419-020-2296-4 [doi] LID - 96 AB - Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8 mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes. FAU - Wang, Xiaofang AU - Wang X AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Chen, Linlin AU - Chen L AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Zhao, Xiaoyan AU - Zhao X AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Xiao, Lili AU - Xiao L AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Yi, Shanting AU - Yi S AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Kong, Yawei AU - Kong Y AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Jiang, Yan AU - Jiang Y AD - Department of Neurology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. jiang120606@163.com. FAU - Zhang, Jinying AU - Zhang J AD - Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China. jyzhang@zzu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200206 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antimicrobial Cationic Peptides) RN - 0 (Antioxidants) RN - 0 (Igf1r protein, mouse) RN - 0 (Tlr9 protein, mouse) RN - 0 (Toll-Like Receptor 9) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - 0 (Cathelicidins) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - Antimicrobial Cationic Peptides/genetics/metabolism/*pharmacology MH - Antioxidants/pharmacology MH - Disease Models, Animal MH - Hypertrophy, Left Ventricular/enzymology/genetics/physiopathology/*prevention & control MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myocardium/*enzymology/pathology MH - Oxidative Stress/drug effects MH - Phosphatidylinositol 3-Kinase/*metabolism MH - Proto-Oncogene Proteins c-akt/deficiency/genetics/*metabolism MH - RNA Interference MH - Receptor, IGF Type 1/*metabolism MH - Signal Transduction MH - Toll-Like Receptor 9/deficiency/genetics/*metabolism MH - Ventricular Function, Left/drug effects MH - Ventricular Remodeling/drug effects MH - Cathelicidins PMC - PMC7005284 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/02/08 06:00 MHDA- 2021/03/10 06:00 PMCR- 2020/02/06 CRDT- 2020/02/08 06:00 PHST- 2019/09/18 00:00 [received] PHST- 2020/01/22 00:00 [accepted] PHST- 2020/01/19 00:00 [revised] PHST- 2020/02/08 06:00 [entrez] PHST- 2020/02/08 06:00 [pubmed] PHST- 2021/03/10 06:00 [medline] PHST- 2020/02/06 00:00 [pmc-release] AID - 10.1038/s41419-020-2296-4 [pii] AID - 2296 [pii] AID - 10.1038/s41419-020-2296-4 [doi] PST - epublish SO - Cell Death Dis. 2020 Feb 6;11(2):96. doi: 10.1038/s41419-020-2296-4.