Investigating the Diagnostic Potential of Vasoconstrictor Peptide for the Detection of Cardiac Pathologies

Abstract

Diabetes induced cardiac pathologies are leading cause of morbidity and mortality around the globe. miRNA-based therapies offering new potential therapeutic and diagnostic options due to their crucial regulatory role in onset and progression of various cardiac diseases. Endothelin-1 (ET-1) has crucial role in development of cardiac hypertrophy can be used as potential diagnostic marker for its detection. The main objective of the study is to investigate mechanistic regulation of miRNA 98-5p mimic in progression of disease and elucidate its cardioprotective role. Our study further investigates diagnostic potential of Endothelin-1(ET-1) for detection of cardiac hypertrophy. Diabetes linked cardiac hypertrophy model was established by administration of streptozotocin (STZ) in rat model and confirmed by histological analysis, heart weight to body weight ratio and heart weight to tibia length ratio. Serum ALT and AST levels, as well as elevated levels of triglycerides and cholesterol, were evaluated for confirmation of safer dose administration. When streptozotocin was induced in rats, it significantly lowers level of antioxidant enzymes and increases levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substance (TBARS) that was observed through biochemical analysis. Real time (qRT) PCR results showed downregulation of miRNA 98-5p and Forkhead Box O3 (FoxO3a) in STZ diabetic rats. Increased expression of endothelin-1 (ET-1), Nuclear factor of activated T-cells (NFAT), myocardin, Bcl-2-like 11 (BIM), cardiac hypertrophic markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in diabetic rats. ET-1 was also downregulated in STZ+miRNA 98-5p treated group suggesting its therapeutic potential in diabetic induced cardiac hypertrophy. Western blot analysis shows decrease protein expression of endothelin-1 and NFATC3 and increase expression of FoxO3a in STZ+miR-98-5ptreated group. To evaluate diagnostic potential of ET-1, total IgG count and endothelin-1 specific antibodies production were analyzed by ELISA in different experimental groups. Total IgG count and endothelin-1 were elevated in disease condition. In conclusion, our results propose that microRNA-98-5p mimic has therapeutic potential for STZ induced cardiac hypertrophy by upregulating the expression of miRNA-98-5p. ELISA results indicated that circulating levels of endothelin-1 are highly upregulated in cardiac hypertrophy. Thus, it may be used as diagnostic biomarker of cardiac hypertrophy and can help in diagnosing disease at early stage before progression to heart failure and death.