Publications (54) View all
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Article: Olmesartan medoxomil treatment potently improves cardiac myosin-induced dilated cardiomyopathy via the modulation of ACE-2 and ANG 1-7 mas receptor.
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ABSTRACT: Angiotensin converting enzyme-2 (ACE-2) is a monocarboxypeptidase that metabolises angiotensin (ANG)-II into angiotensin 1-7 (ANG 1-7), thereby functioning as a negative regulator of the renin-angiotensin system. We investigated whether treatment with ANG-II type 1 receptor blocker, olmesartan medoxomil is associated with the attenuation of cardiac myosin-induced dilated cardiomyopathy (DCM) through recently established new axis of ACE-2/ANG 1-7 mas receptor. DCM was elicited in Lewis rats by immunisation with cardiac myosin, and 28 days after immunisation, the surviving Lewis rats were divided into two groups and treated with either olmesartan medoxomil (10 mg/kg/day) or vehicle. Myocardial protein and mRNA levels of ACE-2, ANG 1-7 mas receptor were upregulated in the olmesartan-treated group compared with those of vehicle-treated DCM rats. In contrast, Olmesartan treatment effectively suppressed the myocardial protein and mRNA expressions of inflammatory markers in comparison to the vehicle-treated DCM rats. Olmesartan treatment significantly reduced fibrosis, hypertrophy and their marker molecules (OPN, CTGF, ANP and GATA-4, respectively), as well as matrix metalloproteinases compared with those of vehicle-treated DCM rats. Enhanced myocardial protein levels of phospho-p38 MAPK, phospho-JNK and phospho MAPKAPK-2 in the vehicle-treated DCM rats were prevented by olmesartan treatment. In addition, olmesartan treatment significantly lowered the protein expressions (Nitrotyrosine, p47phox and p67phox) and superoxide radical production compared with those of vehicle-treated DCM rats. Our present study might serve as a new therapeutic target of DCM in cardiovascular diseases and cardiac myosin-induced DCM via the modulation of ACE-2/ANG 1-7 mas receptor axis in rats with DCM after myosin-immunisation.Free radical research 04/2012; 46(7):850-60. · 2.22 Impact Factor -
Article: Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein.
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ABSTRACT: Autophagy is an intracellular process in which a cell digests its own constituents via lysosomal degradative pathway. Though autophagy has been shown in several cardiac diseases like heart failure, hypertrophy and ischaemic cardiomyopathy, the role and the regulation of autophagy is still largely unknown. Bcl-2-associated athanogene (BAG-1) is a multifunctional pro-survival molecule that binds with Hsp70/Hsc70. In this study, myocardial adaptation to ischaemia by repeated brief episodes of ischaemia and reperfusion (I/R) prior to lethal I/R enhanced the expression of autophagosomal membrane specific protein light chain 3 (LC3)-II, and Beclin-1, a molecule involved in autophagy and BAG-1. Autophagosomes structures were found in the adapted myocardium through electron microscopy. Co-immunoprecipitation and co-immunofluorescence analyses revealed that LC3-II was bound with BAG-1. Inhibition of autophagy by treating rats with Wortmannin (15 microg/kg; intraperitoneally) abolished the ischaemic adaptation-induced induction of LC3-II, Beclin-1, BAG-1 and cardioprotection. Intramyocardial injection of BAG-1 siRNA attenuated the induction of LC3-II, and abolished the cardioprotection achieved by adaptation. Furthermore, hypoxic adaptation in cardiac myoblast cells induced LC3-II and BAG-1. BAG-1 siRNA treatment attenuated hypoxic adaptation-induced LC3-II and BAG-1, and abolished improvement in cardiac cell survival and reduction of cell death. These results clearly indicate that myocardial protection elicited by adaptation is mediated at least in part via up-regulation of autophagy in association with BAG-1 protein.Journal of Cellular and Molecular Medicine 10/2008; 13(2):373-87. · 4.13 Impact Factor -
Article: Inhibition of ref-1 stimulates the production of reactive oxygen species and induces differentiation in adult cardiac stem cells.
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ABSTRACT: Redox effector protein-1 (Ref-1) plays an essential role in DNA repair and redox regulation of several transcription factors. In the present study, we examined the role of Ref-1 in maintaining the redox status and survivability of adult cardiac stem cells challenged with a subtoxic level of H2O2 under inhibition of Ref-1 by RNA interference. Treatment of cardiac stem cells with a low concentration of H2O2 induced Ref-1-mediated survival signaling through phosphorylation of Akt. However, Ref-1 inhibition followed by H2O2 treatment extensively induced the level of intracellular reactive oxygen species (ROS) through activation of the components of NADPH oxidase, like p22( phox ), p47( phox ), and Nox4. Cardiac differentiation markers (Nkx2.5, MEF2C, and GATA4), and cell death by apoptosis were significantly elevated in Ref-1 siRNA followed by H2O2-treated stem cells. Further, inhibition of Ref-1 increased the level of p53 but decreased the phosphorylation of Akt, a molecule involved in survival signaling. Treatment with ROS scavenger N-acetyl-L-cysteine attenuated Ref-1 siRNA-mediated activation of NADPH oxidase and cardiac differentiation. Taken together, these results indicate that Ref-1 plays an important role in maintaining the redox status of cardiac stem cells and protects them from oxidative injury-mediated cell death and differentiation.Antioxidants & Redox Signaling 09/2008; 11(3):589-600. · 8.20 Impact Factor -
Article: Hemodynamic effects of carvedilol infusion and the contribution of the sympathetic nervous system in rats with heart failure.
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ABSTRACT: We investigated the contribution of the sympathetic nervous system (SNS) in maintaining the blood pressure and in regulating the cardiac function during and after carvedilol administration in rats with heart failure (group F). Left ventricular end-diastolic pressure, percent functional shortening, and rates of intraventricular pressure rise were significantly changed by carvedilol infusion as compared with the basal values in group N (normal rats), but not in group F. The left ventricular end-diastolic pressure was elevated, corresponding to the enhancement of the plasma norepinephrine (NE) concentration caused by carvedilol infusion, in group N. The enhancement of the plasma NE concentration induced by carvedilol administration in group F was higher than that in group N. The value for the maximal hypertensive effect of NE intravenous infusion (Emax) was decreased, and the plasma NE concentration at half-maximal effect (EC50) was increased in group F as compared with the values in group N. These results indicate that the SNS (presynaptic) activity is increased and that the SNS receptor sensitivity in the cardiovascular regulation system is decreased in heart failure.Pharmacology 12/2004; 72(4):213-9. · 1.79 Impact Factor -
Dataset: Iron Induced Remodeling in Cultured Rat Pulmonary Artery Endothelial Cells f
