A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα.

Abstract

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.

• Authors: Xiaofang Wang, Linlin Chen, Xiaoyan Zhao, Lili Xiao, Shanting Yi, Yawei Kong, Yan Jiang, Jinying Zhang
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 2 Pg. 96 (02 06 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32029708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antimicrobial Cationic Peptides
• Antioxidants
• Igf1r protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 9
• Phosphatidylinositol 3-Kinase
• Receptor, IGF Type 1
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases
• Cathelicidins

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antimicrobial Cationic Peptides (genetics, metabolism, pharmacology)
• Antioxidants (pharmacology)
• Disease Models, Animal
• Hypertrophy, Left Ventricular (enzymology, genetics, physiopathology, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (enzymology, pathology)
• Oxidative Stress (drug effects)
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (deficiency, genetics, metabolism)
• RNA Interference
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction
• Toll-Like Receptor 9 (deficiency, genetics, metabolism)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)
• Cathelicidins