Activated cardiac fibroblasts (myofibroblast; myoFBs) are crucial players in excessive fibrosis, which ultimately results in myocardial stiffness and heart failure development. Thus, regulation of fibroblasts activation and associated fibrosis would be a potential therapeutic strategy in the treatment of cardiac diseases. Previous studies suggest that in addition to resident fibroblasts, bone marrow fibroblast progenitor cells (FPCs) may home to the failing heart and contribute to excessive fibrosis. The overall goal of this application is to determine the role of BM-derived FPCs and their paracrine signaling (via exosomes) on pressure overload (PO)-induced cardiac fibrosis, and to determine whether inhibition of function of this cell population results in the reduction of cardiac fibrosis and remodeling. We have reported that PO-induced cardiac fibrosis is attenuated by systemic IL10 treatment and IL10-knockout mice (IL10 KO) display exaggerated cardiac fibrosis. But the precise mechanism of anti-fibrotic role of IL10 is not well defined. Thus we hypothesized that ?IL10 inhibits fibroblast progenitor cell (FPCs) homing and trans-differentiation into myoFB and modifies FPC pro-fibrotic paracrine signaling thereby reducing cardiac fibrosis and improving cardiac function?. We will use WT (some with GFP reporter system), IL10 KO, TGFbr1/2 KO and CCR2KO (RFP reporter system) mice in this study. In SA1, via bone marrow transplantation strategy, we will determine whether FPC contributes in Ang II-induced cardiac fibrosis in WT and IL10 Knock out mice and whether IL10 treatment inhibits it.
In specific aim 2 we will identify the TGFb downstream signaling targets [both canonical (Smad2/3), non-canonical (ERK-MAP kinase) and miR associated with fibrosis] and their roles in FPC's trans-differentiation. To identify their role, we will infect/transfect dominant negative adenovirus or kinase-dead construct (Smad/ERK) or antagomir (miRs) with their respective control in WT and IL10KO FPCs.
In specific aim 3 we propose to study the paracrine regulation of FPCs on resident cardiac fibroblast activation and exaggerated fibrosis in IL10KO mice. In this aim we will explore whether pro-fibrotic factors secreted by FPC (WT/IL10KO) via exosomes, induce cardiac fibroblast transition to myoFB. To translate this finding in preclinical settings, in specific aim 3 we will investigate whether transplantation of exosomes-derived from ex vivo-modified FPC (for target miRs/proteins) in IL10 KO mice heart inhibits Ang II-induced fibrosis. The significance of this study is to identify the novel mechanism(s) of IL10 in regulation of cardiac fibrosis. Our proposed experiments can potentially identify novel therapeutic strategies for cardiac repair based on manipulation of bone marrow fibroblast progenitor cells signaling after pressure overload-induced cardiac injury.

Public Health Relevance

): Heart failure is still the leading cause of morbidity and mortality in United States. Cardiac fibrosis is a hallmark for hypertrophic heart failure and its regulation could significantly improve mortality associated with this number one killer disease in USA. Previously, others and we have shown that IL10 acts as a critical regulator of cardiac fibrosis. In this proposal, we will investigate whether IL10 and its downstream signaling targets can modulate fibroblast progenitor cell-mediated fibrosis and facilitate cardiac repair, thereby identifying a novel regulator and target of cardiac repair to treat heart failure. The results of this proposal will therefore be highly relevant for improving public health and improving the length and quality of life of millions of patients with hypertrophic heart disease and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Adhikari, Bishow B
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Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
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Verma, Suresh Kumar (2018) Glycogen synthase kinase 3? helps heart to pump better in obese patients. Int J Cardiol 259:166-167
Rai, Rahul; Verma, Suresh K; Kim, David et al. (2017) A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. Epigenetics 12:1004-1013
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