The tumor suppressor RASSF1A modulates inflammation and injury in the reperfused murine myocardium

Jamie Francisco,Jaemin Byun,Yu Zhang,Olivia Berman Kalloo,Wataru Mizushima,Shinichi Oka,Peiyong Zhai,Junichi Sadoshima,Dominic P Del Re

doi:10.1074/jbc.ra119.008970

Abstract

Inflammation is a central feature of cardiovascular disease, including myocardial infarction and heart failure. Reperfusion of the ischemic myocardium triggers a complex inflammatory response that can exacerbate injury and worsen heart function, as well as prevent myocardial rupture and mediate wound healing. Therefore, a more complete understanding of this process could contribute to interventions that properly balance inflammatory responses for improved outcomes. In this study, we leveraged several approaches, including global and regional ischemia/reperfusion (I/R), genetically modified mice, and primary cell culture, to investigate the cell type-specific function of the tumor suppressor Ras association domain family member 1 isoform A (RASSF1A) in cardiac inflammation. Our results revealed that genetic inhibition of RASSF1A in cardiomyocytes affords cardioprotection, whereas myeloid-specific deletion of RASSF1A exacerbates inflammation and injury caused by I/R in mice. Cell-based studies revealed that RASSF1A negatively regulates NF-κB and thereby attenuates inflammatory cytokine expression. These findings indicate that myeloid RASSF1A antagonizes I/R-induced myocardial inflammation and suggest that RASSF1A may be a promising target in immunomodulatory therapy for the management of acute heart injury.

Highlights

Inflammation is a central feature of cardiovascular disease, including myocardial infarction and heart failure
Aberrant inflammation is thought to underlie a host of pathologies, including those related to cardiovascular disease such as atherosclerosis, injury caused by myocardial infarction (MI),3 and the progression to heart failure [1]
Our previous work demonstrated that cardiomyocytespecific deletion of RASSF1A (RASSF1AF/F;␣MHC-Cre and referred to hereafter as RASSF1A CKO), but not systemic RASSF1A deletion (RASSF1AϪ/Ϫ), attenuated cardiac hypertrophy, remodeling, and dysfunction in response to pressure overload (PO) stress [13]

Summary

Introduction

Inflammation is a central feature of cardiovascular disease, including myocardial infarction and heart failure. Our results revealed that genetic inhibition of RASSF1A in cardiomyocytes affords cardioprotection, whereas myeloid-specific deletion of RASSF1A exacerbates inflammation and injury caused by I/R in mice. Cell-based studies revealed that RASSF1A negatively regulates NF-␬B and thereby attenuates inflammatory cytokine expression These findings indicate that myeloid RASSF1A antagonizes I/R-induced myocardial inflammation and suggest that RASSF1A may be a promising target in immunomodulatory therapy for the management of acute heart injury. Systemic RASSF1A deletion resulted in augmented cardiac fibrosis and did not afford cardioprotection against PO-induced heart failure [13, 14]. These results indicated cell type specificity of RASSF1A signaling that facilitated robust effects on cardiac remodeling and dysfunction. In vivo genetic manipulation to elucidate cell type– specific functions of RASSF1A in this cardiac injury model has not been reported

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Conclusion