Cathelicidin-WA ameliorates diabetic cardiomyopathy by inhibiting the NLRP3 inflammasome.

Abstract

Cathelicidin-WA (CWA) is a novel cathelicidin peptide isolated from snakes that has been suggested to exert anti-inflammatory effects. The aim of our study was to investigate whether cathelicidin-WA (CWA) could protect the heart from diabetic cardiomyopathy (DCM). Streptozotocin (STZ) injection was used to establish a mouse model of DCM. CWA peptide (2 mg/kg or 8 mg/kg) was continuously administered to the mice from 10 weeks to 16 weeks after STZ injection. The mice in the DCM group exhibited cardiac dysfunction, while 8 mg/kg CWA ameliorated this cardiac dysfunction. Cardiac fibrosis, inflammation, and oxidative stress as well as cardiomyocyte apoptosis in the DCM mice were decreased by treatment with 8 mg/kg CWA. We isolated neonatal rat cardiomyocytes and stimulated the cells with high glucose to establish an in vitro model of myocyte cell injury. Consistently, CWA inhibited high glucose-induced cell death, inflammation and oxidative stress in the myocytes. Moreover, CWA reduced the formation of the NLR family pyrin domain-containing 3 (NRLP3) inflammasome by regulating thioredoxin-interacting protein expression and p65 activation. NLRP3 overexpression inhibited the beneficial effects of CWA on the heart during DCM and on high glucose-induced myocyte injury. In summary, CWA attenuates cardiac injury and preserves cardiac function during DCM by targeting the NLRP3 pathway.Abbreviations: AAV9: Adeno associated virus; AGE: Advanced Glycation End products; CWA: Cathelicidin-WA; DCM: diabetic cardiomyopathy; Gpx: glutathione peroxidase; HG: high glucose; IL: Interleukin; NLR: Family Pyrin Domain Containing 3 (NRLP3); TXNIP: Thioredoxin interacting protein; LVEF: left ventricular ejection fraction; MDA: Malondialdehyde; MnSOD: manganese superoxide dismutase; NADPH: Nicotinamide adenine dinucleotide phosphate; NAC: N-acetyl-cysteine; NRCMs: Neonatal rat cardiomyocytes; ROS: reactive oxygen species; STZ: Streptozotocin; TNFa: tumor necrosis factor a.

• Authors: Meng Peng, Yuan Liu, Yawei Xu, Li Li, Yan Li, Haibo Yang
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 20 Issue 21 Pg. 2278-2290 (11 2021) ISSN: 1551-4005 [Electronic] United States
• PMID: 34585633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Cell Cycle Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nlrp3 protein, rat
• Reactive Oxygen Species
• TXNIP protein, rat
• Cathelicidins

Topics

• Animals
• Antimicrobial Cationic Peptides
• Cell Cycle Proteins
• Diabetes Mellitus
• Diabetic Cardiomyopathies (metabolism)
• Inflammasomes (metabolism)
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Stroke Volume
• Ventricular Function, Left
• Cathelicidins