Ph.D. 2006, Banaras University
Courtesy appointment in the Department of Anesthesiology
Specialty: MicroRNomics of cardiovascular diseases and diabetic cardiomyopathy
Major Interest: Understanding the mechanism of heart failure in diabetic set up using innovative approaches including miRNA and stem cell with the goal to develop intervention tool to ameliorate cardiomyopathy.
Diabetes has emerged as a global epidemic. It is an independent cause of cardiomyopathy and when accompanied with other heart disease, it exacerbates cardiac dysfunction and increases the incidence of heart failure. Despite scientific advancement, the number of pre-diabetic and diabetic populations are rapidly increasing, which warrants novel approaches to control diabetes and diabetes- mediated morbidity and mortality. MicroRNAs (miRNAs) are a novel class of non-coding RNAs that modulate gene expression mostly by translational repression. Differential expression of miRNAs are associated with diabetes and cardiovascular diseases. The major interest of our laboratory is to determine candidate miRNAs involved for diabetic cardiomyopathy and to use them as an intervention tool to ameliorate diabetic heart failure. The pathological remodeling in diabetic hearts is accompanied by inflammation, induction of hypertrophy and fibrosis, deregulation of autophagy, and concomitant upregulation of pro-inflammatory cytokines, matrix metalloproteinase-9, homocysteine, and downregulation of beta-adrenergic signaling and contractile proteins. We are interested in understanding the role of candidate miRNAs in regulation of pathological remodeling in diabetic hearts.
High fat diet (HFD) and sedentary life style contribute to diabetes and cardiomyopathy. Exercise has been shown to decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines, however the effect of this cytokine profile change on HFD-induced cardiomyopathy is not fully understood. Similarly, hydrogen sulfide is reported to have cardioprotective effects. One of our research interests is to understand the underlying molecular mechanisms for HFD- mediated cardiomyopathy and how that can be ameliorated by exercise training or treatment with hydrogen sulfide donor.
We are also interested to understand the role of miRNAs and MMP9 in cardiac stem cell survival, proliferation, and differentiation in diabetic set up. MiRNAs and specific transcription factors contribute to trans-differentiation of fibroblast into cardiomyocytes. However, their roles in diabetic hearts is unclear. One of our research interests is to understand the underlying molecular mechanisms of trans-differentiation of fibroblast into cardiomyocytes in diabetic hearts.
High glucose depolarizes mitochondrial membrane potential (Δᴪm) as demonstrated by JC1 staining in HL1 cardiomyocytes (red polarized and green depolarized mitochondria), which may lead to mitochondrial degradation by mitophagy. Mitophagy is accompanied by fusion of mitochondria with adapter molecule p62 and then fusion of autophagosome with lysosome, which can be assessed by lysosome- associated membrane glycoprotein- 2 (LAMP2). The co-localization of mitochondria with lysosome and monodansylcadaverin (marker of acidic vesicle) indicates increased mitophagy, which can be corroborated by transmission electron micrographs (middle panel). Increased mitophagy may contribute to pathological remodeling such as hypertrophy, which is evaluated by wheat germ agglutinin staining that demarcates cell boundaries (bottom left panel). The cardiac dysfunction is determined by magnetic resonance imaging (bottom right panel).Recent publications:
- Kesherwani V, Shahshahan HR, Mishra PK. Cardiac transcriptome profiling of diabetic Akita mice using microarray and next generation sequencing. PLOS One. 2017 Aug 24; 12(8):e0182828. PMID: 28837672
- Nandi SS, Mishra PK. H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes. Scientific Reports. 2017; 7: 3639. PMID: 28623294
- Mishra PK, Ying W, Nandi SS, Bandyopadhyay GK, Patel KS, Mahata SK. Diabetic cardiomyopathy: an immunometabolic perspective. Frontiers in Endocrinology, section Cellular Endocrinology. 2017; 8: 72. PMID: 28439258
- Nandi SS, Zheng H, Sharma NS, Shahshahan HR, Patel KP, Mishra PK. Lack of miR-133a decreases contractility in diabetic hearts: a role for novel cross-talk between tyrosine aminotransferase and tyrosine hydroxylase. Diabetes. 2016 Oct, 65 (10): 3075-90. PMID: 27411382
- Prathipati P, Metreveli N, Nandi SS, Tyagi SC, Mishra PK. Ablation of Matrix Metalloproteinase-9 Prevents Cardiomyocytes Contractile Dysfunction in Diabetics. Front Physiol. 2016 Mar 15; 7:93. PMID: 27014091
- Nandi SS, Duryee MJ, Thiele GM, Anderson DR, Mishra PK. Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanism unloading. American Journal of Translational Research 7(4) 683-696, 2015. PMID:26064437