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

ABSTRACT 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.