Evolution of ß-catenin-independent Wnt-GSK3-mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model.

OBJECTIVE: Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event's revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/ß-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases. METHOD: Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3ß mediator. RESULT: The GSK-3ß could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3ß by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents. CONCLUSION: We hereby discuss a novel therapeutic role of the ß-catenin independent, Wnt-GSK3-mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.

Calcium sensing receptor as a novel target for treatment of sepsis induced cardio-renal syndrome: Need for exploring mechanisms.

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.