Kallistatin Improves Lipid Metabolism and Alleviates Cardiac Hypertrophy via the SIRT1/PPAR Pathway: An Experimental Study

Cardiovascular disease is a major health concern, with cardiac hypertrophy (CH) leading to heart failure and increased mortality. Although kallistatin has shown a protective effect against cardiovascular diseases, its role in CH remains unclear. The effects of kallistatin on myocardial lipid metabolism, inflammation, and hypertrophy via the SIRT1/PPARα pathway in both animal model and cell culture were assessed. The rat model of CH was induced by Angiotensin II (Ang II). Plasma kallistatin and inflammatory indicators (IL-6, TNF-α, MCP-1) were measured using ELISA. In Vitro, Ang II-treated NRVMs were divided into control, Ang II, and Ang II + kallistatin groups. WGA-Oregon Red staining was used to assess cell size, and CO-IP was performed to evaluate SIRT1/PPARα interactions. Gene (ANF, α-SKA, PDK4, mCPT-I, MCAD) and protein expression in NRVMs and heart tissues were analyzed via qRT-PCR and Western blot. Kallistatin levels were decreased in patients with CH and rats with Ang II-induced CH. In Vivo, kallistatin treatment decreased the HW/BW ratio, SBP, DBP and MAP, cardiomyocyte size, and arrhythmias. In Vitro, kallistatin reversed Ang II-induced hypertrophy, evidenced by smaller cell size (via WGA-Oregon Red staining), reduced ANF and α-SKA expression, and decreased lipid accumulation. Kallistatin inhibited inflammatory markers (IL-6, TNF-α, MCP-1) and enhanced fatty acid oxidation by upregulating PDK4, mCPT-I, and MCAD. CO-IP demonstrated interactions between SIRT1 and PPARα, and pathway inhibition confirmed that kallistatin's protective effects were mediated through the SIRT1/PPARα pathway. Kallistatin protects against CH and arrhythmias reducing inflammation and improving lipid metabolism by modulating the SIRT1/PPARα pathway.