The loss of cardiomyocytes through necrosis and apoptosis in response to ischemia and reperfusion (I/R) is a critical factor leading to myocardial remodeling and loss of cardiac function. However, attempts at limiting cardiomyocyte death through broad-based inhibitors have yet to produce an effective treatment for patients with acute MI. We propose that this approach ignores the unique functionality and crosstalk that occurs between cell types and therefore fails to provide cardioprotection. In other words, while death of cardiomyocytes is deleterious to the myocardium during I/R, apoptosis of select cells is beneficial. Despite being a sterile environment, both innate and adaptive immune responses are activated by I/R in the myocardium. This is important because a well-orchestrated inflammatory response is necessary to clear debris, activate reparative cells and promote wound healing after I/R. However, excessive and/or prolonged inflammation can augment matrix degradation, impair collagen deposition, cause greater CM loss, extend infiltrate to non-infarcted myocardium, increase fibrosis and worsen heart function. Therefore, maintaining a balanced inflammatory response is critical to provide maximum cardioprotection. It is reasonable to posit, then, that defective inflammatory cell apoptosis could function as a """"""""faulty brake"""""""" and cause an excessive immune response and worsened injury. RASSF1A is a pro-apoptotic molecule and known tumor suppressor, yet nothing is known regarding RASSF1A and inflammation. Our preliminary results implicate RASSF1A as an important modulator of inflammation in the myocardium during I/R. This proposal will examine the possibility that altered inflammatory cell apoptosis due to RASSF1A downregulation contributes to myocardial injury following I/R. We hypothesize that the ablation of a critical endogenous apoptotic signaling cascade, i.e. a heightened resistance to cell death, in cells of hematopoietic origin is detrimental to the myocardium during I/R. To test our hypothesis, we will employ the culture of primary macrophages from WT and Rassf1A KO mice and a macrophage cell line to attain mechanistic insight regarding their activation and survival in vitro. Importantly, these studies will be complimented by in vivo experiments utilizing bone marrow transplantation and simulated I/R in WT and KO mice. Importantly, the findings obtained upon successful completion of this proposal will have the potential to shift the medical paradigm away from general inhibitors of cell death toward cell type-specific therapies for ischemic heart disease and acute MI.
Ischemic heart disease is a major cause of morbidity and mortality worldwide. Although much has been learned regarding ischemic heart disease, the underlying mechanism leading to heart muscle cell death and scar formation is not fully known, resulting in treatments that are ineffective. Furthermore, how the interaction between heart muscle cells and non-cardiac cell types (i.e. inflammatory cells) can modulate the progression of heart disease is poorly understood. This grant application proposes to investigate a novel signaling mechanism involving RASSF1A and its ability to regulate inflammatory cell activation and apoptosis during ischemia/reperfusion (I/R) injury in the heart. Specifically, how RASSF1A represses inflammation and promotes apoptosis in macrophages will be examined. By investigating this novel aspect of RASSF1A signaling, this proposal will identify new targets for intervention that may lead to improved treatment of ischemic heart disease in patients.
|Matsuda, Takahisa; Zhai, Peiyong; Sciarretta, Sebastiano et al. (2016) NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart. Circ Res 119:596-606|
|Del Re, Dominic P (2015) Erratum to: The hippo signaling pathway: implications for heart regeneration and disease. Clin Transl Med 4:53|
|Yang, Yanfei; Del Re, Dominic P; Nakano, Noritsugu et al. (2015) miR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival. Circ Res 117:891-904|
|Wackerhage, Henning; Del Re, Dominic P; Judson, Robert N et al. (2014) The Hippo signal transduction network in skeletal and cardiac muscle. Sci Signal 7:re4|
|Del Re, Dominic P; Matsuda, Takahisa; Zhai, Peiyong et al. (2014) Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell 54:639-50|
|Del Re, Dominic P; Sadoshima, Junichi (2014) Elucidating ERK2 function in the heart. J Mol Cell Cardiol 72:336-8|