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ABSTRACT
Year : 2016  |  Volume : 2  |  Issue : 4  |  Page : 19-22

Young Scientists Award Session


Date of Web Publication8-Apr-2016

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How to cite this article:
. Young Scientists Award Session. J Pract Cardiovasc Sci 2016;2, Suppl S1:19-22

How to cite this URL:
. Young Scientists Award Session. J Pract Cardiovasc Sci [serial online] 2016 [cited 2020 Aug 4];2, Suppl S1:19-22. Available from: http://www.j-pcs.org/text.asp?2016/2/4/19/179936

Targeting Mirna-33a to Ameliorate Cardiac Remodelling in Dilated Cardiomyopathy

Anupam Mittal, Santanu Rana 1 , Rajni Sharma, Vikas Arige 2 , Sanskriti Khanna 3 , Nitish Mahapatra 2 , Sagartirtha Sarkar 1 , Uma N. Saikia 4 , Ajay Bahl,

Shyamal K. Goswami 5 , Madhu Khullar 3


Departments of Cardiology, 3 Experimental Medicine and Biotechnology and 4 Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 1 Department of Zoology, University of Calcutta, Kolkata, West Bengal, 2 Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 5 School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Background: Myocardin (MYOCD), a potent transcriptional co-activator of smooth muscle (SM) and cardiac genes, is upregulated in failing myocardium in animal models and human end-stage heart failure (HF). However, the role of miRNAs regulating MYOCD expression in heart failure remains unknown. We sought to identify the miRNAs regulating the cardiac MYOCD and to study the molecular and functional consequences of cardiac modulation of MYOCD specific miRNA in an animal model of HF/DCM. Approach and Results: Our study design included identification and validation of miRNA targeting MYOCD using in silico approach and 3'-UTR luciferase reporter assays and to study its cardiac expression in idiopathic DCM (IDCM) endomyocardial biopsies, renal artery ligation (RAL) rat model of HF/DCM. We identified and validated miRNA-33a as a putative regulator of MYOCD expression in cardiomyocytes. Cardiac miRNA-33a expression was significantly decreased in IDCM and in RAL. We also investigated if cardiac specific augmentation of miRNA-33a expression using a homing peptide conjugated siRNA could potentially ameliorate the cardiac remodelling and outcome in RAL. We observed that targeted modulation of miRNA-33a attenuated cardiac hypertrophy and fibrosis and ameliorated the impaired diastolic dysfunction in RAL model of cardiomyopathy. Conclusion and Significance: This data provides the first evidence that miRNA-33a is involved in regulating cardiac MYOCD expression as well as regulation of cardiac remodelling process and cardiac-specific augmentation of miRNA-33a offers a putative therapeutic target in DCM.

Molecular Basis of Oxidative Stress-induced Increase in AT1 Receptor Gene Expression in Cardiac Fibroblasts

V. Anupama, K. Shivakumar


Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Angiotensin II (Ang II) is an important determinant of cardiac and vascular pathology associated with hypertension, cardiac hypertrophy, coronary heart disease and congestive heart failure. The AT1 receptor mediates the manifold actions of Ang II. As a major source of extracellular matrix proteins, matrix metalloproteinases and several growth factors and cytokines, cardiac fibroblasts influence multiple aspects of myocardial pathophysiology. Notably, the regulatory role of Ang II in cardiac fibroblasts is a major determinant of the structural and functional integrity of the heart following injury. The pro-fibrogenic effects of Ang II are mediated by the AT1 receptor whose expression in cardiac fibroblasts surpasses that in myocytes. Against this backdrop, this study probed the molecular mechanisms that link altered redox status to AT1 expression in cardiac fibroblasts. H 2 O 2 enhanced AT1 expression via NADPH oxidase-dependent reactive oxygen species induction. Activation of NF-κB and AP-1, abolition of AT1 expression upon their inhibition, and their ability to bind to the AT1 promoter confirmed transcriptional control of AT1 by NF-κB and AP-1 in H2 O 2 -treated cells. Inhibition of the MAPKs showed that while ERK1/2 and p38 MAPK suffice for NF-κB activation, all three kinases are required for AP-1 activation and in turn augmented AT1 expression. To conclude, oxidative stress enhances AT1 expression in cardiac fibroblasts by a complex mechanism involving the coordinated action of NF-kB, AP1 and MAPKs. Importantly, by causally linking oxidative stress to AT1 up-regulation in cardiac fibroblasts, this study offers a novel perspective on the pathogenesis of cardiovascular diseases associated with oxidative stress.

Effect of CDR-267-F018 Against Dyslipidemia Induced Cardiovascular Complications in ApoE KO Atherosclerotic Model

Kanshana J. S., Rebello S. C., Pathak P, Nageswararao K, M. N. Srivastava 1 , T. Narender 2 , A. K. Dwivedi 3 , Kumaravelu J, M. K. Barthwal, M. Dikshit


Pharmacology Division, 1 Botany Division, 2 Medicinal and Process Chemistry Division, 3 Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India

Effect of CDR-267-F018, a fraction isolated from xylocarpus moluccensis was investigated in an ApoE KO model of accelerated atherosclerosis in the present study. ApoE KO mice were kept on 0.15% cholesterol and 21% fat diet (12079B Research Diets, USA) for 12 weeks to accelerate the atherosclerosis progression. CDR-267-F018 (50mg/kg/day) or vehicle was administered by oral route in ApoE KO mice for another 6 weeks. Increase in the circulating lipids (TC and LDL p < 0.001vs HFD) was significantly prevented in CDR-267-F018 treated group. Moreover, significant increase in eNOS mRNA expression following CDR-267-F018 treatment improved acetylcholine induced relaxation (p < 0.01vs HFD) as well aortic lipid accumulation (p < 0.01vs HFD) was also significantly reduced (p < 0.01vs HFD). Concomitantly, reduction in CD68, MCP-1 mRNA expression and augmemtation of collagen content (type 1 & III) in the aortic plaques was evident in CDR-267 treated group, suggesting protective effect of CDR-267 towards plaque stabilization. In addition following treatment with CDR-267- F018, aortic inflammatory markers such as TNF-α, IFN-γ, IL-6 and iNOS mRNA expression were significantly attenuated and anti-inflammatory cytokine, IL-10 was enhanced as compared to HFD fed group. Assessment of cardiac function by echocardiography in all the test groups, indicated significant improvement in cardiac functional parameters such as LV mass, cardiac output in CDR-267-F018 treated as compared to HFD group (p < 0.01vs HFD). Results obtained in the present study indicate protective role of CDR267-F018 against dyslipidemia, atherosclerotic progression and cardiovascular dysfunction in ApoE KO mice.

Reversible Lysine Acetylation of c-Jun NH2-Terminal Kinase Regulates Insulin Resistance in Diabetic Heart

Mohsen Sarikhani, Chaithra Sanjeev, Donald Wolfgeher 1 , Mahesh P. Gupta 1 , Nagalingam Ravi Sundaresan


Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India, 1 Department of Surgery, University of Chicago, Chicago, IL, USA

Type 2 diabetes mellitus is one of the major risk factors for cardiovascular disease. Type 2 diabetes is a defect in which body becomes resistant to the effects of insulin. In general insulin binds to insulin receptors and activates downstream PI3K/Akt signaling to induce glucose uptake in cardiomyocytes. However, cardiomyocytes from diabetic patients fail to respond to insulin, a phenomenon known as insulin resistance, considered as a key trigger for the development of diabetic cardiomyopathy. Studies indicate that insulin resistance develops in diabetic hearts due to the chronic elevated activity of c- Jun NH2-terminal kinase (JNK), which inhibits IRS-1, a component of PI3K/Akt signaling. However, reason for chronic hyperactivation of JNK during insulin resistance is not completely understood. In this study, we developed a high fat-high sucrose diet (HF-HSD)-induced type 2 diabetic model. 12 weeks of HF-HSD induced significant cardiac remodeling and contractile dysfunctions in mice. Our molecular analysis reveals significantly reduced acetylation of JNK in diabetic hearts, which is correlated with elevated activities of JNK. Next, we performed mass spectrometry-based proteomic analysis and found JNK as an acetylated protein. Interestingly, acetylation of JNK at Lys153 inhibits ATP binding and autophosphorylation. Furthermore, our results suggest that acetyl transferase p300 interacts and inhibits catalytic activity of JNK. On the other hand, SIRT2, a class III lysine deacetylase localized in cytoplasm, deacetylates and activates JNK, promotes inhibitory phosphorylation of IRS-1 and thus, inhibits glucose uptake and insulin sensitivity. Inhibition of SIRT2 by small molecules inhibitors, promotes glucose uptake in insulin-resistant myocytes and reverse insulin resistance. Collectively, our results suggest that reversible acetylation of JNK at Lys153 plays a critical role in the development of insulin resistance in diabetic cardiomyocytes.

Poly ADP-Ribosylation of Akt Regulates Insulin Signaling in Heart

Sneha Mishra, Chaithra Sanjeev, Nagalingam Ravi Sundaresan


Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India

Diabetic heart under the influence of high circulating glucose, lipids and hormones develop insulin resistance, lipotoxicity, mitochondrial dysfunction and apoptosis. It is well recognized that the activity of Akt kinase, a serine/threonine-specific protein kinase core to IGF/insulin signaling, is impaired in end-stage failing hearts of diabetic patients. Defective Akt signaling is believed to be the major cause for the development of diabetic cardiomyopathy (DCM). However, the reason behind the impairment of Akt in diabetic hearts is not yet fully understood. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification, where ADP-ribose adducts are added to target proteins by poly (ADP-ribose) polymerases (PARPs). PARP1, a major nuclear isoform of PARPs, is involved in the DNA repair, telomere maintenance and transcription. However, recent reports indicate that PARP-1 is hyperactive in several chronic diseases, including diabetes. In this work, we demonstrate that PARP-1 poly(ADP-ribosyl)ates Akt and inhibits its nuclear activity in heart. Our findings indicate that PARP-1 enzymatic activity is increased several fold in type 2 diabetic hearts, which is inversely correlated with Akt phosphorylation. PARP-1 binds to Akt kinase and poly(ADP-ribosyl)ates it. Overexpression of wild type PARP1, but not its catalytic mutant significantly reduced the phosphorylation of Akt and its downstream targets, GSK-3β, and FoxO. On contrast, PARP-1 deficiency causes spontaneous activation of Akt and its targets. Further molecular analysis indicated that Akt is poly(ADP-ribosyl)ated at E40 and E49 residues of pleckstrin homology domain. Interestingly, unregulated poly(ADP-ribosyl)ation impairs Akt membrane localization, a critical event required for Akt phosphorylation and activation. Overall, our findings suggest a novel modification of Akt, which is critical for the development of insulin resistance during diabetes.

Effects of Impaired Glucose Tolerance on Vasculogenic Potential of Peripheral Blood Mononuclear Cells

Mallu Abhiram Charan Tej, Abel Arul Nathan 1 , Viswanathan Mohan 2 , Ranjani Harish 2 , S. B. Anand 1 , Madhulika Dixit


Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, 2 Department of Diabetology, Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialities Center, Chennai, 1 Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, Tamil Nadu, India

Progression of an individual from normal (NGT) to impaired glucose tolerance (IGT) to type-2 diabetes is accompanied by worsening abnormalities in the glucose metabolism. Asian Indians seem to go down this path a decade earlier than the western counterparts. Although it is known that the numbers of circulating angiogenic progenitors is low in these conditions, the effects of impaired glucose metabolism on the function of PBMCs are not known. The objective of this study was to characterize the peripheral blood mononuclear cells (PBMCs) from drug naοve NGT and IGT subjects for their vasculogenic and endothelial differentiation potential. Of the 61 subjects recruited for the study, based on oral glucose tolerance test (OGTT), 30 subjects exhibited normal and 31 subjects exhibited impaired glucose tolerance. The IGT subjects also exhibited insulin resistance as shown by HOMA-IR index. They also showed low reactive hyperemia index (RHI) post occlusion and high levels of circulating soluble Tie-2 (sTie-2) in serum, two markers for endothelial dysfunction. Cell culture analysis of fresh PBMCs from fasting samples of IGT subjects showed decreased adhesion to fibronectin, migration and endothelial tube incorporation abilities compared to NGT. Upon 7 day culture in endothelial differentiation medium, progenitors from IGT attained endothelial phenotype similar to those from NGT; however, the nitric oxide (NO) production was significantly lower in IGT. Semi quantitative RT-PCR analysis showed decreased expression of Integrin-β2, CXCR4 and increased arginase-2 expression in IGT samples.

Identification of Epigenetic and Proteomic Markers of Dilated, Hypertrophic and Restrictive Cardiomyopathy in Peripheral Blood

Subhoshree Ghose 1,2 , Swati Varshney 1,2 , Vinay Singh Tanwar 1 , Sourav Ghosh 1,2 , Sanjana Pillai 1 , Sandeep Seth 3 , Shantanu Sengupta 1,2

1 Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, 2 Academy of Scientific and Innovative Research, 3 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Introduction: Cardiomyopathy is a complex broad-spectrum disease of the myocardium with unknown etiology. It is majorly classified into three categories, dilated (DCM), hypertrophic (HCM) and restrictive cardiomyopathy (RCM), based on pathophysiological phenotype. Recent studies suggest that gene-environment interactions play a major role in their manifestation. We have used plasma proteomics approach to identify proteomic markers and also have profiled the DNA methylome in three different forms of myopathy. Methodology: Plasma samples from DCM, HCM, RCM and controls were immunodepleted and three sets of 4-plex iTRAQ based quantitative LC-MS proteomic experiments undertaken to identify the differentially expressed proteins. For methylome profiling, methylated DNA immunoprecipitation sequencing was performed to identify differentially methylated regions. Results and Discussions: We have identified a total of 208, 191 & 211 proteins in three different replicate experiments at 1% FDR. A total of 69, 61 and 62 differentially expressed proteins were found, out of which 31, 35 and 31 were up regulated and 38, 27 and 31 were down-regulated in DCM, RCM and RCM respectively as compared to controls. Further, a total of 8 up and 8 down-regulated proteins were common among three groups. Up-regulated proteins are involved in complement and blood coagulation cascade. Down-regulated proteins are involved in lipoprotein metabolism and reverse cholesterol pathway. MeDIP analysis revealed several regions that are differentially methylated. Conclusions: This study is unique because identifying DNA methylation and proteomic markers in peripheral blood would circumvent the complications in identifying markers in tissue biopsies.

Clinical Significance of Collagen Metabolism Markers in Rheumatic Heart Valve Disease in Indian Subpopulation

Tanima Banerjee, Somaditya Mukherjee, Sudip K. Ghosh 1 , Monodeep Biswas 2 , Santanu Datta 3 , Sanjib Pattari 4 , Shelly Chatterjee, Arun Bandyopadhyay


Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 1 General Medicine Department, Medical College, Kolkata, West Bengal, India, 2 Department of Cardiology, Geisinger Community Medical Center and Wright Center for Graduate Medical Education, Scranton, PA, USA, 3 Department of Cardio-thoracic and Vascular Surgery, Institute of Post Graduate Medical Education and Research, SSKM Hospital, 4 Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, India

Rheumatic Heart Disease (RHD) is a chronic acquired disorder. It is a condition in which the heart valves are damaged by rheumatic fever. Mitral valve is mostly affected in RHD, and this disease is more prevalent in low and middle income countries. The present study was conducted to investigate whether extracellular matrix remodelling of the mitral valve alters the levels of circulating biomarkers of collagen metabolism in rheumatic heart disease. The study involved Indian subpopulation of rheumatic heart disease subjects before and after valve replacement surgery which includes age and sex matched controls. Periodic clinical monitoring was performed with echocardiography. Circulating levels of markers of collagen turnover were assessed by immunoassays and histopathology was conducted to examine the tissue architecture and occurrence of fibrosis. A p value <0.05 was considered statistically significant. Plasma PICP and PIIINP concentrations increased significantly (p < 0.01) in MS and MR subjects compared to controls but decreased gradually over a one year period post mitral valve replacement (p < 0.05). PICP was undetectable in control urine but was detected in urine of RHD subjects. Receiver operating characteristic curve analysis established PICP as a better marker (AUC = 0.95; 95% CI = 0.91 - 0.99; p < 0.0001). It has been found that the rate of collagen turnover is high resulting in significant elevation of biomarkers of collagen metabolism. Therefore, monitoring plasma PICP may guide new strategies to disease management and can be clinically used to diagnose or monitor disease progression in Rheumatic heart disease.

Serum Cortisol: A Biomarker to Assess the Oncoming Event of Stress Related Acute Myocardial Infarction in Type 2 Diabetics and in Hypertensive Patients

D. D. Venkatesh Babu, G. Velmurugan, S. Ramasamy


Department of Molecular Biology, School of Biological Sciences, Madurai Kamaraj University, Madurai, Tamil Nadu, India

Cardiovascular Diseases (CVDs) are the number one cause of death, globally. An estimated 17.5 million people died from CVDs in 2012, accounting for 31% of all mortality. Stress is one of the major risk factors for CVDs. 33% of heart attacks happen due to depression. Serum Cortisol is a stress hormone that is secreted in excess from adrenal cortex during stress condition. Type-2 diabetics and hypertensive patients are prone to Acute Myocardial Infarction [AMI] because of stress. Our objective is to find out a cutoff value for stress marker serum cortisol, to assess the oncoming event of AMI. For this, serum cortisol was measured in samples of AMI patients [n = 61] and in controls [n = 143] by ECLIA. Results: The ROC curve analysis revealed the serum cortisol as a reliable marker to find stress level among AMI patients. [Area under curve as 0.8006, 95% CI - 0.7165-0.8846, P < 0.0001]. Mann Whitney Two- tailed test showed significant association of serum cortisol level between AMI patients and controls [For AMI patients 95% CI - 16.59-22.97, Mean- 19.78 ΅g/dL. For controls 95% CI - 9.622-10.57 Mean - 10.09. P < 0.0001]. Our conclusion is that serum cortisol is significantly associated with AMI and the cutoff of 19.78 ΅g/dL can serve as a biomarker to assess the oncoming event of AMI either in Type-2 diabetic or in hypertensive patients.




 

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