Novel therapeutic targets AMI ? Antonio Abbate, MD, PhD Improving the treatment of acute myocardial infarction (AMI) to prevent heart failure (HF) and death remains an urgent unmet medical need. The AHA estimates that every 42 seconds an American will have an AMI, and despite the improvement in treatment and prognosis, a significant number of patients continue to die. Moreover, AMI survivors are not healthy individuals, and are indeed at significantly higher risk of developing HF. The AHA estimates that approximately 17 years of years of life are lost due to AMI: 20% of patients will have new onset HF within 5 years, with an estimated mortality for those patients of >50% at 5 years. With a rising prevalence (nearly 6,000,000 subjects, 2% of US population), and high incidence (>900,000 new cases per year in USA alone)[1], AMI and HF are important public enemies. We propose to explore a novel target for intervention in AMI aimed at modulating the delicate death-survival balance in the myocardium that has been subject of sub-lethal injury. Prompt reperfusion has revolutionized the treatment of AMI. The restoration of flow in the occluded coronary artery salvages a large amount of myocardium at risk, reducing infarct size and its consequences. Reperfusion, however, may however lead to incomplete salvage, associated with the no-reflow phenomenon, and not all the events occurring with reperfusion are beneficial. Based on experimental data, it is expected that a strategy aimed at limiting reperfusion injury in AMI ?would reduce infarct size by a further 25%, realizing the full benefit of reperfusion?. Clinical attempts to use ischemic preconditioning, remote ischemic pre-conditioning, or post-conditioning in clinical trials have failed. We therefore propose novel target for intervention that is different from the ?early? mitochondrial events, targeting the myocardium that has been subject of sub-lethal injury. Low-density lipoprotein receptor related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger receptor for serine protease inhibitors (SERPINs) and as regulatory receptor leading to an anti- inflammatory and pro-survival signal. We propose a novel therapeutic strategy to inhibit the inflammatory injury early during reperfusion in AMI by enhancing LRP1 signaling using targeted agonists. We propose to study the (1) Role of physiologic LRP1 signaling in experimental AMI, by studying mice with genetic LRP1 disruption undergoing experiment AMI and measuring the acute inflammatory response, infarct size, resolution of the inflammation and cardiac remodeling; (2) Role of LRP1 in mediating cardioprotective effects of plasma derived serine protease inhibitors (SERPINs) in experimental AMI, by studying mice with AMI treated with SERPINs and other LRP1 agonists in absence/presence of a LRP1 blocking antibody; (3) Efficacy of treatment strategy using a synthetic oligopeptide, SP16, designed to function as a LRP1 agonist, in experimental AMI in small and large animals.
Novel therapeutic targets AMI ? Antonio Abbate, MD, PhD The American Heart Association estimates that every 42 seconds an American will have an acute myocardial infarction (AMI), and despite the improvement in treatment and prognosis, a significant number of patients continue to die. Moreover, AMI survivors are not healthy individuals, and are indeed at significantly higher risk of developing heart failure (HF). There is therefore an urgent need to find new treatment for AMI and HF. We propose to explore a new target for intervention in AMI aimed at modulating the delicate death-survival balance in the myocardium that has been subject of sub-lethal injury after reperfusion. Low-density lipoprotein receptor related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger receptor for serine protease inhibitors (SERPINs) and as regulatory receptor leading to an anti-inflammatory and pro- survival signal. We propose to enhance LRP1 signaling using targeted agonists leading to the salvage of a greater amount of myocardium and thus preventing HF and favoring survival after AMI.
| Toldo, Stefano; Austin, Dana; Mauro, Adolfo G et al. (2017) Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction. JACC Basic Transl Sci 2:561-574 |
