CVG Lab

CARDIOVASCULAR GENETICS LAB

INDIAN INSTITUTE OF TECHNOLOGY MADRAS

What are Cardiovascular Diseases? Why should these be studied?

Cardiovascular diseases (viz., coronary heart disease, heart failure, stroke, etc.) affect a large section of the young and adult population and are the leading causes of morbidity/mortality worldwide. Recent studies have documented that although the mortalities associated with cardiovascular diseases are declining in high-income countries such as Western Europe and North America, the burden of cardiovascular diseases continues to rise in middle- and low-income countries, including India. Notably, South Asians have a greater prevalence of cardiovascular risk factors than the rest of the world, and India itself is estimated to have more than half of the world’s heart disease patients at present. These diseases not only cause enormous loss of human lives, but also lead to huge health care costs, tremendous socio-economic burden, declining national productivity and quality of life. The determinants of cardiovascular diseases are multifactorial, complex, and often interrelated. Stress, inadequate physical activity, smoking, higher intake of fats and sodium, lower consumption of potassium, fruits and vegetables are well-known risk factors for cardiovascular diseases. Besides these, a strong influence of genes in cardiovascular complications has also been established. Hypertension (elevated arterial blood pressure), dysregulated catecholamine homeostasis, dyslipidemia, increased oxidative stress, cardiac remodeling, and protein misfolding are some of the chief risk factors for cardiovascular diseases. However, the pathogenesis of cardiovascular diseases remains incompletely understood.

We, at the Cardiovascular Genetics Lab, are interested in unravelling the genetic and molecular bases that underlie cardiovascular diseases with an aim for their early diagnosis, prognosis, management and treatment. In this direction, to elucidate how alterations in key genes/molecular factors contribute to disease phenotype, we study human subjects (cases versus controls), utilize rodent models (of hypertension, atherosclerosis and diabetes) as well as perform investigations at the cellular level (employing cultured cell lines). Moreover, we use multidisciplinary approaches to delineate the molecular interactions and signaling pathways that are disrupted in these pathological conditions. We are currently focusing on three broad aspects of cardiovascular complications which will facilitate identification of biomarkers and potential therapeutic agents as outlined below.

What do we do in CVG lab?

Discovery of functional genetic variations in Indian populations and their associations with cardiovascular diseases

We have discovered a number of genetic variants in the chromogranin A gene promoter and exonic regions (that translate to bioactive peptides such as anti-hypertensive/cardioprotective catestatin and dysglycemic pancreastatin) using case-control approach in Indian populations. Chromogranin A expression is dysregulated in several cardiovascular diseases. Linkage disequilibrium analysis and genetic association studies identified several genetic variations in chromogranin A locus that enhance the risk for cardiovascular/metabolic disorders in the Indian population. Furthermore, using various experimental (cellular/biochemical/biophysical/physiological assays), and computational (molecular modelling, molecular dynamic simulations, docking of peptides with their receptors) we demonstrated that these variants alter the expression of chromogranin A or potency of catestatin /pancreastatin peptides. Similarly, we have identified functional variants in the regulatory region of matrix metalloproteinases and established that these variants alter the risk factor for cardiometabolic disorders. Results from these studies provide new insights into the molecular mechanisms contributing to cardiovascular diseases. These studies have implications for development of diagnostic and therapeutic strategies for management of the cardiovascular diseases.

Transcriptional and post-transcriptional regulation of cardiovascular/ metabolic syndrome susceptibility genes

Dysregulated gene expression is the underlying cause for many pathological conditions including cardiovascular diseases. Using a combination of computational tools and cell culture experiments, we have characterized the promoter regions of several candidate genes. We have also identified the roles of transcription factors, microRNAs that are involved in modulating the gene expression. For example, we have identified transcription factors involved in the regulation of Hsp70, renalase, monoamine oxidase A and B. The regulation of renalase gene by transcription factors Sp1, STAT3, and ZBP89 is the first report on the transcriptional regulation of renalase. Similarly, we, also for the first time, reported the involvement of miR-29 and miR-146 in the post-transcriptional regulation of mouse and human renalase gene expression. Besides this, the role of miR-27a in the regulation of Hmgcr and miR-1224, miR-300 in the regulation of MAO-B gene expression at the post-transcriptional level are first reports on the regulation of Hmgcr and MAO-B genes by miRNAs. Interestingly, most of these genes are differentially expressed in human, rodent models of pathological conditions signifying their roles in cardiovascular complications. These findings may lead to the development of novel therapeutic agents for clinical management of cardiovascular complications.

Mechanism of differential expression of candidate genes of cardiometabolic diseases in rodent models

Rodent models are widely used in laboratories due to their sequence similarity with the human genome to gain molecular insights into complex human diseases. We sequence and compare the regulatory regions of various candidate genes implicated in cardiovascular diseases in inbred mouse models of genetic hypertension [viz., Blood Pressure High (BPH), Blood Pressure Normal (BPN) and Blood Pressure Low (BPL) animals]. Through this approach, we identified several novel polymorphisms which offered molecular insights into the genetic basis for the differential expression of candidate genes in these hypertensive models. For example, we have identified polymorphisms in the promoter region of beta-Hydroxy beta-methylglutaryl-CoA (Hmgcr, the rate-limiting enzyme in the cholesterol biosynthesis pathway) and cystathionine gamma-lyase (Cth, a key enzyme involved in endogenous hydrogen sulfide production) genes which altered binding affinities of several transcription factors, such as n-Myc, Max, c-Fos (in the case of Hmgcr) and c-Rel, HOXA3, IRF1 (in the case of Cth) suggesting a role for these transcription factors in essential hypertension. Using a similar approach, we have identified several polymorphisms in the regulatory regions of Hmgcr gene in Spontaneously Hypertensive Rat (SHR, a rat model of genetic hypertension and related cardiovascular complications) as compared to its normotensive control, Wistar Kyoto rat (WKY). These results provide new insights into the mechanisms of regulation of candidate genes in cardiovascular diseases.

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