Fellowship Fanmuyi Yang: The Role of Platelets in Early Pericoronary Inflammation Induced by Transverse Aortic Constriction (TAC)

Hypertension-induced left ventricular (LV) hypertrophy is usually accompanied by intensive cardiac fibrosis, which is considered as a major contributor to arrhythmogenic sudden cardiac death. Emerging evidence suggests that perivascular inflammation contributes to cardiac fibrosis. Using a well-established mice model of LV hypertrophy - transverse aortic constriction (TAC); we have shown an prominent early accumulation of platelets and other inflammatory cells along the coronary arteries shortly after TAC. In our model, immunodepletion of platelets leads to a significant reduction in the recruitment of T lymphocyte to the coronary arteries early (days) and a subsequent increase of alpha-smooth muscle actin content in the vessel wall late (weeks) after TAC. However, the mechanism(s) responsible for platelet accumulation and the subsequent effects of platelets on lymphocytes are not clear. Our recent Masson’s Trichrome staining data demonstrated prominent collagen exposure along the luminal surface of larger coronary arteries early after TAC. Collagen is a potent agonist for platelets by acting on the two major platelet collagen receptors, GPVI and alpha2beta1. In this application, I aim to evaluate the contribution of collagen exposure on platelet recruitment to coronary arteries in the setting of acute pressure overload by testing the role of the major platelet collagen receptors in the process. Aim one: to determine a role of platelet GPVI in TAC-induced early pericoronary inflammation and later LV remodeling. In this aim, I will test the working hypothesis that the exposure of collagen contributes to platelet activation and accumulation along coronary vessels by evaluating the requirement for GPVI in the process. Disrruption of GPVI signaling will be performed by injection of JAQ-1 antibody or JAQ1 Fab fragment. Aim Two: to determine a role of alpha2beta1 in TAC-induced early pericoronary inflammation and later LV remodeling. In this aim, I will test the working hypothesis that if alpha2beta1contributes platelet accumulation along damaged vessels early after TAC. alpha2-/- mice or anti-alpha2 antibody will be used to disrupt Integrin alpha2beta1signaling. In summary, my results should provide new insight into vascular damage and platelet adhesion that occurs in TAC, which may also improve understanding and treatment of hypertensive heart diseases.