Abstract
Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
Highlights
Diabetic cardiomyopathy (DCM) is defined as cardiac structural and functional abnormalities among diabetic individuals independent of hypertension or coronary artery disease, which is mainly characterized as massive cardiomyocyte dropout, interstitial fibrosis, and ventricular dysfunction [1, 2]
OSTN is reduced by AKT/FoxO1 dephosphorylation in diabetic hearts Mice were exposed to repeated STZ injections and the hyperglycemic mice (FBG > 16.6 mmol/L) were kept for additional 12 weeks to trigger cardiac injury after diabetes induction
To investigate the potential involvement of OSTN in DCM progression, we first detected whether cardiac OSTN expression was altered in diabetic samples or cultured cells were prepared in the ice-cold cell lysis buffer without protease inhibitors or detergents, and cell debris was removed by centrifugation at 17,000 × g for 20 min under 4 °C
Summary
Diabetic cardiomyopathy (DCM) is defined as cardiac structural and functional abnormalities among diabetic individuals independent of hypertension or coronary artery disease, which is mainly characterized as massive cardiomyocyte dropout, interstitial fibrosis, and ventricular dysfunction [1, 2]. It is reported as the key pathogenic factor for heart failure and contributes to more than half of diabetic death [3]. These compelling evidences define the proteasome as a promising target to treat DCM
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