Cardiovascular disease is the leading cause of death and pharmacologic treatment strategies have improved cardiovascular outcomes and survival. However, the prognoses of affected individuals remain poor; hence, the need to elucidate underlying mechanisms and develop better therapies for cardiovascular diseases. Our proposed studies focus on circRNA as an unexplored component of the cardiovascular system to yield new understanding and tools for treatment of myocardial infarction. The overarching objective of this current revised application is to reveal how circular RNAs (circRNAs), a recently identified class of RNAs that are generated from many protein-coding genes, impact mouse models of myocardial infarction (MI). Preliminary data generated for the current proposal shows that modulation of a specific circRNA from the Fibronectin Type III Domain Containing 3B (FNDC3b) gene (circFNDC3b) in ischemic myocardium can modulate cardiac repair after myocardial infarction in mice. In particular, we found: 1) decreased circFNDC3b expression in post-MI mouse hearts and in left ventricular tissues of ischemic cardiomyopathy patients, 2) and in endothelial cells and cardiomyocytes in post-MI mouse hearts; 3) AAV9 mediated circFNDC3b overexpression enhances endothelial cell angiogenesis and inhibits hypoxia-induced cardiomyoblast apoptosis in vitro, 4) and improves left ventricular function, remodeling and neovascularization post-MI in mice; 5) circFNDC3b bind RNA binding protein fused in sarcoma (FUS-1) in endothelial cells and cardiomyoblasts and regulate FUS- 1 levels. Our central hypothesis is that rescue of circFNDC3b promotes positive cardiac remodeling after MI by enhancing neovascularization and improves cardiomyocyte cell survival through FUS-1 inhibition, thus improving cardiac function. This research will create a multi-modal platform for future work, accelerating progress in this field as it relates to therapeutic targets and underlying mechanisms. The hypotheses will be tested under the following 3 specific aims:
Specific Aim 1 : To determine the physiological role of circFNDC3b on myocardial injury repair post-MI in mice.
Specific Aim 2 : To elucidate the molecular mechanism by which circFNDC3b regulates cardiomyocyte cell survival and enhances endothelial cell function.
Specific Aim 3 : To develop novel therapeutic strategies to manipulate other circRNAs to promote myocardial injury repair post-MI in mice. Successful completion of the proposed research will potentially identify circRNAs as potentially novel therapeutic targets for ischemic myocardial repair.
Certain diseases like myocardial infarction (MI) are the major cause of mortality in humans. IL-10 is a known cardio-protective cytokine that reduces inflammatory response, protects heart muscle cells and increases new blood vessel formation in the heart after injury. This project aims to understand the role of a newly discovered non-coding RNA known as circularRNAs in the regulation of ischemic heart repair in the context of inflammation and ischemia. Data obtained from proposed studies may potentially be crucial in understanding new mechanisms of ischemic heart repair and potentially identification of inflammation-regulated circularRNAs as new therapeutic targets.
|Sluijter, Joost Petrus Gerardus; Davidson, Sean Michael; Boulanger, Chantal M et al. (2018) Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 114:19-34|
|Garikipati, Venkata Naga Srikanth; Kishore, Raj (2018) Induced Pluripotent Stem Cells Derived Extracellular Vesicles: A Potential Therapy for Cardiac Repair. Circ Res 122:197-198|
|Cheng, Zhongjian; Shen, Xinggui; Jiang, Xiaohua et al. (2018) Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. Redox Biol 16:215-225|
|Gupta, Rajesh; Mackie, Alexander R; Misener, Sol et al. (2018) Endothelial smoothened-dependent hedgehog signaling is not required for sonic hedgehog induced angiogenesis or ischemic tissue repair. Lab Invest 98:682-691|
|Cheng, Zhongjian; Verma, Suresh K; Losordo, Douglas W et al. (2017) Reprogrammed Human Endothelial Cells: A Novel Cell Source for Regenerative Vascular Medicine. Circ Res 120:756-758|
|Sasi, Sharath P; Yan, Xinhua; Zuriaga-Herrero, Marian et al. (2017) Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart. Radiat Res 188:191-203|
|Srikanth Garikipati, Venkata Naga; Kishore, Raj (2017) Young Hearts Run Free: Therapeutic Potential of Neonatal Human Cardiac Progenitor Cells Secretome. Circ Res 120:751-752|
|Verma, Suresh Kumar; Garikipati, Venkata Naga Srikanth; Kishore, Raj (2017) Mitochondrial dysfunction and its impact on diabetic heart. Biochim Biophys Acta Mol Basis Dis 1863:1098-1105|
|Verma, Suresh K; Garikipati, Venkata N S; Krishnamurthy, Prasanna et al. (2017) Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium. Circulation 136:940-953|
|Yue, Yujia; Garikipati, Venkata Naga Srikanth; Verma, Suresh Kumar et al. (2017) Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes. Tissue Eng Part A 23:1241-1250|
Showing the most recent 10 out of 48 publications