Molecular Mechanism of Stress Regulation in Cardiac Dysfunction and Hematopathologies

Abstract

The redox hemostasis regulation is essential for cellular processing and its survival. Uncontrolled regulation of cellular stress related processes and signaling leads to the development of different diseases including cancer and cardiac disorders. To date, numerous clinical and experimental studies proved that oxidative stress play a key role in cellular signaling regulation that contributes in the heart failure and in the several hematopathologies. There is need to find specific therapeutic targets that may normalize the body redox conditions. Although in previously documented studies stress role in cardiac disorder and cancer has been described, but still research is going to address. The excessive free radical generation during disease condition that leads to oxidative stress is believed to play a key role in cardiac dysfunction and hematotoxicity. The persistent oxidative stress due to decreased antioxidants enzymes capacity leads to the damage of macromolecules contributing in several diseases including cardiac complication and hematotoxicity. In the present study the mechanism of redox homeostasis regulation was evaluated in cardiac hypertrophy as well as in hematological complications. Our findings showed that different stress inducers such as hyperglycemia, serotonin, endothelin-1, isoproterenol (ISO) and phenylephrine (PE) generates free radicals that leads to oxidative stress. Redox signaling network also get disturbed during transverse aortic construction (TAC) and calcineurin transgenic (CnA-Tg) cardiac hypertrophic condition, which further participates in the diseases progression. In order to reduce and attenuate the pro oxidative stress ROS, potent antioxidants such as N-acetyl NAC (N-acetyl, L-cysteine) and melatonin effects were investigated in the present study. Our findings also suggests that potent antioxidants have beneficial role in redox homeostasis regulation. MicroRNAs are emerging and key regulator in cardiac disorders. Herein, we proposed that oxidative stress directly or indirectly alters the miRNA expression that contributes in diseases progression. To address this, miRNAs which have direct or indirect link to anti-hypertrophic pathway element including superoxide dismutase (SOD) were predicted and selected. The altered expressions of miRNAs were confirmed in well-established TAC and CnA-Tg cardiac hypertrophic mice model. High expression of miR-132, miR-212, miR-155, miR-17, miR-199b, miR-152, miR- 146b in TAC and miR-212, miR-199b, miR-152 and miR-17 were observed in transgenic mice heart tissue. While miR-142-3p and miR-92b were down regulated in both cardiac hypertrophy models. To determine miRNAs link to oxidative stress, their Abstract Molecular mechanism of stress regulation in cardiac dysfunction and hematopathologies XII expressions were observed in HL-1 cells treated with hydrogen peroxide. Dose dependent high expression of miR-132, miR-212, miR-152, miR-199b, miR-155 and miR-146b were observed. While the miR-142-3p as well as miR-17 were down regulated upon hydrogen peroxide treatment. Further, miRNAs expression were observed in the presence and absence of potent antioxidants (NAC and melatonin) in ISO and ET-1 induced cardiac hypertrophy model. miR-152 expression in the presence of potent antioxidant remained unchanged both in ET-1 and ISO induced cardiac hypertrophy model while miR-132 and miR-212 was down regulated in presence of potent antioxidants. The earlier down regulated miR-142-3p in ISO and ET-1 induced hypertrophic model was up regulated in the presence of NAC as well as in melatonin group suggesting oxidative stress link to miRNAs regulation. Previous studies reported the role of trace elements in diverse physiological and pathological systems, but their effects as leading cause of leukemia in Pakistani population have not still been addressed. The present investigation also aimed to determine the level of oxidative stress regulating trace elements (Fe, Zn, Cu and Ni) as well as ROS and SOD status in acute leukemia patients from the Pakistani population. The concentrations of free radicals in both AML as well as ALL were significantly higher compared to the normal healthy individuals. Serum SOD levels were significantly down regulated in acute leukemia patients. Trace element Fe and Zn concentrations were significantly decreased while the concentrations of Cu and Ni were increased in leukemia patients compared to the normal healthy subjects. The ROS level and blast cells count were higher in disease control groups than in groups treated with varying amounts of B. persicum extract and the normal group. Moreover, there was an imbalance in hematological parameters in untreated and treated groups with a correlation between free radicals and plant extract administration. In summary, many pathological condition accompanied with excessive ROS production and deficiency in antioxidant defense that leads to oxidative stress which further participate in disease progression including cardiac and hematological disorders. Regulation of oxidative stress offering a possible therapeutic approach for cardiac and hematological disorders.