Post-ischemic cardiac remodeling

Monasky, Michelle

Abstract

The signaling cascades which become activated during post-ischemic cardiac remodeling are poorly understood. One protein which we have previously shown to be cardioprotective during acute ischemia/reperfusion injury is p21-activated kinase 1 (Pak1), a serine/threonine kinase. Our objective is to determine the functional significance of the Pak1/MAPKs and Wnt/?-catenin signaling cascades during post-ischemic myocardial remodeling to promote amelioration of the depressed myocardial mechanics. Our approach involves the use of a Pak1-KO mouse model of post-ischemic myocardial remodeling obtained through irreversible left anterior descending (LAD) coronary artery ligation for 10 weeks. This knowledge will advance the field by providing a significant contribution in the understanding of Pak-1's role in regulating maladaptive control of cardiac contractility. The training program has been developed in an environment fully supportive of the intellectual and practical aspects of achieving the proposed aims. The project is carried out in close association with investigators in the Center for Cardiovascular Research and a Program Project Grant as well as side by side with trainees and research faculty in our labs, who measure and think about a broad spectrum of questions from integrative cell signaling and structural biology, single cell and myofilament mechanics, in situ and ex vivo heart mechanics, metabolism, proteomics and lipidomics. The project and our training program has the objective of broadening Michelle's perspectives on control of heart muscle contraction in relation to downstream signaling to elements critical in excitation contraction coupling and to apply this understanding and perspective to translational medicine. The investigation involves potential translation to treatment or prevention of the consequences of coronary artery diseases and post-MI complications. We have established a mentoring committee for Michelle who meets with her 2 to 3 times a year formally and ad hoc as the need arises. Near the time of her transition to an independent pathway we will meet as often as necessary to offer advice in planning and coping with this transition. Survival skills and preparation for the transition in terms of extramural funding of grants such as AHA SDG and K99/ROO grants are discussed and considered.

Public Health Relevance

Sometimes a blockage occurs in vessels that normally provide oxygen and nutrients to the heart muscle, which causes parts of the heart to become damaged or even die. As a result, over time, even weeks or months later, the heart grows (hypertrophies) to try to compensate for the damaged area, which is no longer working normally, but in most instances the patients'conditions are so severe that this compensatory mechanism is no longer sufficient, and this leads to heart failure. We are studying the changes that occur during this process so we can better help patients in the long-term recovery after a heart attack.