Novel application potential of cinaciguat in the treatment of mixed hyperlipidemia through targeting PTL/NPC1L1 and alleviating intestinal microbiota dysbiosis and metabolic disorders

• Published in: Pharmacological research Vol. 194; p. 106854
• Main Authors: Jia, Ang, Jiang, Hongfei, Liu, Wenjing, Chen, Pengwei, Xu, Qi, Zhang, Renshuai, Sun, Jufeng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2023; Elsevier
• Subjects: Cinaciguat; Dual inhibitors; Gut microbiota; Niemann–Pick C1-like 1; Pancreatic triglyceride lipase; PCoA; Gut microbiota; RU; EDC; LDL-C; OTUs; HFD; PTL; HDL-C; SPR; NPC1L1; Dual inhibitors; MD; NHS; Niemann–Pick C1-like 1; H&E; RMSD; PLS-DA; Pancreatic triglyceride lipase; PCA; Cinaciguat; Cinaciguat (PubChem CID: 9808022); NBD-cholesterol; F/B; 4-MU; 4-MUO; pancreatic triglyceride lipase; dual inhibitors; cinaciguat; gut microbiota
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2023.106854

Mixed hyperlipidemia, characterized by high levels of triglycerides and cholesterol, is a key risk factor leading to atherosclerosis and other cardiovascular diseases. Existing clinical drugs usually only work on a single indicator, decreasing either triglyceride or cholesterol levels. Developing dual-acting agents that reduce both triglycerides and cholesterol remains a great challenge. Pancreatic triglyceride lipase (PTL) and Niemann–Pick C1-like 1 (NPC1L1) have been identified as crucial proteins in the transport of triglycerides and cholesterol. Here, cinaciguat, a known agent used in the treatment of acute decompensated heart failure, was identified as a potent dual inhibitor targeting PTL and NPC1L1. We presented in vitro evidence from surface plasmon resonance analysis that cinaciguat interacted with PTL and NPC1L1. Furthermore, cinaciguat exhibited potent PTL-inhibition activity. Fluorescence-labeled cholesterol uptake analysis and confocal imaging showed that cinaciguat effectively inhibited cholesterol uptake. In vivo evaluation showed that cinaciguat significantly reduced the plasma levels of triglycerides and cholesterol, and effectively alleviated high-fat diet–induced intestinal microbiota dysbiosis and metabolic disorders. These results collectively suggest that cinaciguat has the potential to be further developed for the therapy of mixed hyperlipidemia. [Display omitted] •Cinaciguat showed treatment potential for mixed hyperlipidemia through targeting PTL and NPC1L1.•Cinaciguat reduced high-fat diet induced increases in lipid accumulation, body weight, and hyperlipidemia.•Cinaciguat effectively alleviated high-fat diet induced intestinal microbiota dysbiosis and metabolic disorders.