The potential role of LCZ696 in ameliorating diabetic cardiomyopathy by inhibiting the myocardial inflammation, ER stress, and apoptosis through the RAGE/NF‐κB and PERK/CHOP signaling Pathways

Abstract

The development of diabetic cardiomyopathy (DCM) is multifactorial that leads to myocardium structural and functional disruption resulting excessive activity of the renin‐angiotensin system (RAS) and finally heart failure. LCZ696 newly established as chronic heart failure drug which combines a neprilysin inhibitor (sacubitril) and an angiotensin II receptor blocker (valsartan). Present study is designed to find the effect of LCZ696 on DCM in rats. Diabetes was induced by feeding rats with a high‐fat diet for 6 weeks following a single injection of STZ (30mg/kg). Diabetic rats were randomly divided in three group (n=8), LCZ696 and valsartan treatment was started two weeks after the DM induction and continued for 8 consecutive weeks. Blood pressure of individual rats was recorded using tail‐cuff instruments. At end of the treatment echocardiography was done. In serum glucose, insulin, creatine kinase‐MB and lactate dehydrogenase (LDH). In cardiac tissues, pro‐inflammatory cytokines and advanced glycation end‐products (AGEs) formation estimated. Western blot and RT‐PCR were used to determine the apoptotic genes, endoplasmic reticulum stress (ER) parameters. LCZ696 and valsartan ameliorated the DCM progression by inhibiting of AGEs, its receptor (RAGE) at mRNA, pro‐apoptotic gene markers (BAX and caspase‐3) associated with induction of the antiapoptotic gene (Bcl‐2) at mRNA and protein expressions, NF‐κB at the mRNA and protein levels associated with restoring the elevation of pro‐inflammatory cytokines such as TNF‐α, IL‐6, and IL‐1β at the activity level. Furthermore, LCZ696 and valsartan helps in restoring the induction of ER stress parameters (GRP78, PERK, eIF2a, ATF4, and CHOP) at the mRNA and protein levels. LCZ696 and valsartan improved diastolic dysfunction and attenuated histological abnormalities. LCZ696 and valsartan attenuated DCM by inhibiting the myocardial inflammation, ER stress, and apoptosis through the RAGE/NF‐κB and PERK/CHOP signaling cascades. Collectively, present results revealed LCZ696 has more strong protective effect against DCM than valsartan.