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Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (dp/dt max.) and minimum developed pressure (dp/dt min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat's heart. Also, septic rat's heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.

Calcium sensing receptor (CaSR) is localized in various organs and plays diverse physiological and pathological roles. Several scientific contributions have suggested the involvement of this cell surface receptor in cardiac and renal diseases. Sepsis is considered to be one of the major causes of ICU admissions. Cardiac dysfunction and acute kidney injury are major manifestations of sepsis and associated with reduced survival. Presently, the treatment approaches for management of sepsis induced cardiac depression and kidney injury are not satisfactory. Activation of CaSR has been demonstrated to induce cardiomyocyte damage upon lipopolysaccaharde (LPS) exposure by enhancing calcium ion levels, ROS (reactive oxygen species) production, promotion of inflammation and apoptosis. In addition, CaSR seems to be a critical regulator of intracellular calcium ion levels, which is directly implicated in induction of mitochondrial dysfunction and release of various pro-apoptotic pathways during sepsis. Certain evidences have also documented the expression of CaSR on neutrophils and T lymphocytes, where it is involved in activation of neutrophils and induces apoptosis of immune cells. Moreover, the expression of CaSR has been confirmed in podocytes, mesangial cells, proximal tubular cells and its activation is responsible for podocyte effacement, mesangial cell proliferation and proximal tubular cell apoptosis. We have analyzed the existing evidences, and critically discussed the possible mechanisms underlying CaSR activation mediated cardiac and renal dysfunction in sepsis condition., (© 2021 Wiley Periodicals, LLC.)