Inhibition of transglutaminase 2 (TG2) ameliorates ventricular fibrosis in isoproterenol-induced heart failure in rats

作者：Doa’a Al-u’datt, Carole C. Tranchant, Muhammad H. Alu’datt, Sara Abusara, Ahmed Al‐Dwairi, Mohammad Alqudah, Othman Al‐Shboul, Roddy Hiram, Yasemin Altuntaş, Saied A. Jaradat, Karem H. Alzoubi · 发表于：Life Sciences · 年份：2023 · DOI：10.1016/j.lfs.2023.121564 · 被引用次数：11 · 研究领域：Blood properties and coagulation、Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors

AIMS: Transglutaminase (TG) inhibitors represent promising therapeutic interventions in cardiac fibrosis and related dysfunctions. However, it remains unknown how TG inhibition, TG2 in particular, affects the signaling systems that drive pathological fibrosis. This study aimed to examine the effect TG inhibition by cystamine on the progression of isoproterenol (ISO)-induced cardiac fibrosis and dysfunction in rats. MATERIALS AND METHODS: Cardiac fibrosis was established by intraperitoneal injection of ISO to rats (ISO group), followed by 6 weeks of cystamine injection (ISO + Cys group). The control groups were administered normal saline alone or with cystamine. Hemodynamics, lipid profile, liver enzymes, urea, and creatinine were assessed in conjunction with heart failure markers (serum NT-proANP and cTnI). Left ventricular (LV) and atrial (LA) fibrosis, total collagen content, and mRNA expression of profibrotic markers including TG2 were quantified by Masson's trichrome staining, LC-MS/MS and quantitative PCR, respectively. KEY FINDINGS: Cystamine administration to ISO rats significantly decreased diastolic and mean arterial pressures, total cholesterol, triglycerides, LDL, liver enzymes, urea, and creatinine levels, while increasing HDL. NT-proANP and cTnI serum levels remained unchanged. In LV tissues, significant reductions in ISO-induced fibrosis and elevated total collagen content were achieved after cystamine treatment, together with a reduction in TG2 concentration. R...