Thorp Project Summary Abstract-Resubmission. Heart failure after acute myocardial infarction (AMI) is a significant cause of morbidity and mortality. Though pharmacological advances have significantly reduced mortality, the residual risk of post AMI-induced heart failure is increasing. This compels the development of new approaches to preserve the integrigty of cardiac tissue after injury. The extent of tissue damage in the acute phase of AMI is a critical determinant of the degree of subsequent adverse remodeling that leads to impaired cardiac performance. As such, an important goal is to minimize infarct size and its expansion, which are a function of cardiomyocyte death and ineffecient tissue repair. Efficient phagocytic removal of dying cardiomyocytes by efferocytosis is critical to initiating resolving inflammation and to heart healing. For example, reduced efferocytosis of dying cardiomyocytes is directly correlated with increased morbidity and mortality post AMI. Recent studies have also shown macrophage subsets to be differentially responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the molecular pathways within myocardial phagocytes that regulate efferocytosis-directed inflammation resolution in the heart, remain unknown. The Thorp laboratory has made the recent discovery that maladaptive inactivation of efferocytosis signaling pathways worsen heart repair after AMI, paving the way for a new class of molecular targets to enhance heart healing. Our studies newly reveal that the apoptotic cell receptors of the TAM family, MerTK and AXL, surprisingly act though distinct mechanisms to regulate cardiomyocyte efferocytosis and myocardial inflammation resolution. Our data in non-gene targeted mice and humans also suggest that AXL is naturally inhibited during AMI by proteolysis. These initial findings led to important new lines of investigation. This includes: (I) The degree to which AXL uniquely functions in macrophages to regulate AMI repair in the hypoxic heart, including how this may be exploited for thereapeutic intervention. (II) Novel TAM receptor-dependent and -independent immunometabolic mechanisms of efferocytosis and inflammation resolution and (III) the unknown causal role of AXL proteolysis post AMI in mice and patients. Thus, these new Aims are poised to make significant advances in the still relatively understudied process of efferocytosis in heart, efferocytic immunometabolic signaling, and the basic biology of TAM receptors. Newly created tools, including novel gene-engineered experimental animals, will assist in rigorous testing of the aforementioned principles and are of significance to both cardiac inflammation and broader principles of tissue injury.

Thorp Narrative Lay Efferocytosis is the phagocytic clearance and metabolism of dying cells. This process is triggered by immune cell receptors to activate tissue repair. Inefficient efferocytosis, such as during a heart attack, is permissive for increased cell death and loss of contractile heart function that leads to heart failure. The studies outlined herein are among the first to test the therapeutic potential, mechanistic basis, and clinical relevance of efferocytosis after heart attack.