Rho signaling in the development and treatment of myocardial infarction complication
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abstract
Modern reperfusion technology, thrombolytic treatment, and neurohormonal blockade therapy have significantly decreased the overall mortality of acute myocardial infarction (MI) including severe clinical complications like left ventricular aneurysm (LVA) in the past decades. However, the patients with the complications continue to face catastrophic consequences, and they often develop deteriorating heart failure and/or intractable arrhythmias. Surgical intervention is the major therapeutic option. However, the survival rate was less than half in the patients with congestive heart failure or arrhythmias. There is no specific pharmacological treatment due to the lack of effective druggable target. Using unbiased protein screening assay in LVA patients, we discovered that Rnd3, a ubiquitously expressed Rho GTPase and Rho kinase 1 (ROCK1) inhibitor, may function as a unique factor preventing MI-induced LVA, and the manipulation of Rnd3-mediated Rho signaling could be a new therapeutic target. The incidence of LVA is significant, given the fact that there are approximately 1.5 million heart attack cases in the United States each year. Prevention of this sever post-MI complication is a critical need. The development of preventative therapeutics requires a detailed understanding of the involved molecular mechanisms of the complication, which must rely on extensive bench investigations and clinically relevant animal models. In this study, an Rnd3 deficient-mouse line that is susceptible to heart attack-induced LVA is developed. The mouse model shows several features that are observed in human LVA patients; such as an overactive inflammatory response and an increased incidence of LVA in aged mice; all of which provides an ideal animal model for the mechanistic study. Multiple systemic approaches are proposed, which includes in vitro analysis of cell culture experiments, and in vivo genetic animal assessments with loss- and gain-of-function strategies to investigate the relationship between the expression levels of Rnd3 and LVA formation. The mechanistic findings from this proposal should result in clinical implications. The study will establish a connection between the expression of a genetic factor and the occurrence of LVA. This novel concept will provide a potential diagnostic test and a new target for the prevention of LVA. The project has basic and clinical translational significance for the understanding of this life-threatening complication.
