Small Engine, Big Power: MicroRNAs as Regulators of Cardiac Diseases and Regeneration

Joladarashi, Darukeshwara; Thandavarayan, Rajarajan Amirthalingam; Babu, Sahana Suresh; Krishnamurthy, Prasanna

doi:10.3390/ijms150915891

Cited by 47 publications

(44 citation statements)

References 140 publications

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“…MicroRNAs (miRNAs) play key regulatory role in diverse biological process during development, physiology and disease, including HF [16]. miRNA target prediction analysis identified that ELAVL1 harbors complementary binding sites for several miRNAs including miRNA-9 (Position 675–682 and 2818–2825).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

Jeyabal

Thandavarayan

Joladarashi

et al. 2016

Biochemical and Biophysical Research Communications

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132

106

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Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to heart failure (HF). ELAV-like protein 1 (ELAVL1) plays a critical role in the progression of inflammation and HF. However the role of ELAVL-1 in inflammation induced cardiac cell death (pyroptosis) under hyper glycemic condition remains elusive. Our data demonstrates that ELAVL1 expression augmented with a concomitant increase in caspase-1 and IL-1 beta expression in human hearts and human ventricular cardiomyocytes under hyperglycemic condition. Furthermore, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Interestingly, miRNA-9 expression significantly reduced in high glucose treated cardiomyocytes and in human diabetic hearts. Inhibition of miR-9 upregulates ELAVL1 expression and activates caspase-1. Alternatively, treatment with miR-9 mimics attenuates hyperglycemia-induced ELAVL1 and inhibits cardiomyocyte pyroptosis. Taken together our study highlights the potential therapeutic implications of targeting miR-9/ELAVL1 in preventing cardiomyocyte cell loss during HF in diabetics.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

Jeyabal

Thandavarayan

Joladarashi

et al. 2016

Biochemical and Biophysical Research Communications

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132

106

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“…In the pathological form, the size of the heart initially increases to compensate for the damage to cardiac tissue, but later leads to a decline in left ventricular function [52]. Pathological hypertrophy has been extensively studied and reviewed in relation to miRNAs that are present in the heart [18, 43]. To understand the specific role of miRNAs in cardiac hypertrophy, van Rooij et al have reported the first microarray analysis data using two different animal models of pathological cardiac hypertrophy.…”

Section: Mirnas In Cardiovascular Diseasesmentioning

confidence: 99%

MicroRNA: A new therapeutic strategy for cardiovascular diseases

Samanta

Balasubramanian

Rajasingh

et al. 2016

Trends in Cardiovascular Medicine

109

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Myocardial infarction, atherosclerosis and hypertension are the most common heart-related diseases that affect both the heart and the blood vessels. Multiple independent risk factors have been shown to be responsible for cardiovascular diseases. The combination of a healthy diet, exercise and smoking cessation keeps these risk factors in check and helps maintain homeostasis. The dynamic monolayer endothelial cell integrity and cell-cell communication are the fundamental mechanisms in maintaining homeostasis. Recently, it has been revealed that small non-coding RNAs (ncRNAs) play a critical role in regulation of genes involved in either posttranscriptional or pretranslational modifications. They also control diverse biological functions like development, differentiation, growth, and metabolism. Among ncRNAs, the short interfering RNAs (siRNAs) and microRNAs (miRNAs) have been extensively studied, but their specific functions remain largely unknown. In recent years, miRNAs are efficiently studied as one of the important candidates for involvement in most biological processes and have been implicated in many human diseases. Thus, the identification and the respective targets of miRNAs may provide novel molecular insight and new therapeutic strategies to treat diseases. This review summarizes the recent developments and insight on the role of miRNAs in cardiovascular disease prognosis, diagnostic and clinical applications.

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“…Recently, micro ribonucleic acids (miR) (∼20-22 nucleotide small RNAs) have elicited substantial interest as regulators of and therapeutic targets for HF (6). MiR dysregulation after cardiac injury has been implicated in several biological processes involved in cardiovascular diseases (7,8).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury

Joladarashi

Garikipati

Thandavarayan

et al. 2015

Journal of the American College of Cardiology

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Background Micro ribonucleic acid (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress. Objectives This study sought to explore the role of miR in human CD34+ cell (hCD34+) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions. Methods In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells (EPC) was analyzed using a polymerase chain reaction-based miR microarray. MiR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on hCD34+ cell angiogenic proteome profile, in vitro and on cardiac repair and function after I-R injury in immunodeficient mice. Results The miR array data from EPCs in response to inflammatory stimuli indicate changes in numerous miR with a robust decrease in miR-377. Human cardiac biopsies from HF patients showed significant increase in miR-377 expression compared to nonfailing control hearts. Proteome profile of hCD34+ cells transfected with miR-377 mimics showed significant decrease in proangiogenic proteins versus nonspecific control transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual-luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377-silenced hCD34+ cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular (LV) function. Conclusions These findings indicate that HF increases miR-377 in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34+ cells into ischemic myocardium promoted their angiogenic ability, attenuating LV remodeling and cardiac fibrosis.

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Small Engine, Big Power: MicroRNAs as Regulators of Cardiac Diseases and Regeneration

Cited by 47 publications

References 140 publications

MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

MicroRNA: A new therapeutic strategy for cardiovascular diseases

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury

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