Transcriptomic and epigenetic response to cardiac injury

The limited regenerative capacity of the postnatal mammalian heart represents a major challenge in cardiovascular disease. Cardiomyocytes lost or functionally compromised as a consequence of congenital heart defects or myocardial infarction are insufficiently replaced, potentially contributing to the development of heart failure. Understanding the mechanisms underlying cardiomyocyte adaptation to cardiac stress and injury is therefore essential for identifying strategies to promote cardiac regeneration. This thesis investigates cardiomyocyte responses to abnormal cardiac loading during postnatal development and following myocardial infarction. First, current knowledge of cardiomyocyte proliferation and cardiac regenerative capacity during development and postnatal life is reviewed. Subsequently, the effects of early volume overload on cardiomyocyte cell-cycle activity and transcriptional profiles are investigated in a postnatal mouse model. Adaptation of the juvenile right ventricle to pressure overload is examined in rats, including the potential effects of neuregulin-1 on cardiomyocyte proliferation and cardiac function. Furthermore, cardiomyocytes located in the border zone surrounding infarcted myocardium are characterized using transcriptomic and epigenetic approaches. These studies identify distinct molecular properties of border zone cardiomyocytes and further define their active regulatory landscape following myocardial infarction. Together, this thesis provides insight into the cellular, transcriptional, and epigenetic responses of cardiomyocytes to cardiac stress and injury, contributing to a better understanding of mechanisms that may ultimately be exploited to promote regeneration of the mammalian heart. Show more