Cathelicidin-WA ameliorates diabetic cardiomyopathy by inhibiting the NLRP3 inflammasome

Cell Cycle. 2021 Nov;20(21):2278-2290. doi: 10.1080/15384101.2021.1981631. Epub 2021 Sep 29.

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.

Keywords: Cathelicidin-WA; NF-κB p65; NLRP3; diabetic cardiomyopathy; thioredoxin interacting protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • 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

Substances

  • 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

Grants and funding

This work was supported by the National Natural Science Foundation of China (grant nos. 81172405 and 81572490), the Tianjin Science and Technology Committee (grant no. 18JCZDJC98600) and the Science and Technology fund of Tianjin Binhai New Area Health and Family Planning Commission (grant no. 2018BWKZ002).