Linking Extracellular Matrix Stiffness With Cardiomyocyte Structure And Function

The composition and organization of the extracellular matrix (ECM) provides cues to myocardial cells that direct normal function and responses to stress. However, little is known about how exactly a change in environmental tension leads to alterations in cardiomyocyte cell size and contractile force. Collagen I comprises the majority of cardiac ECM where it is crosslinked and matured by the lysyl oxidase (LOX) family of enzymes that includes LOX and LOX-like (LOXL) proteins. LOX and LOXLs are frequently upregulated in the heart after injury, and their inhibition has been shown to alleviate increases in tissue stiffness. Cardiac injury models result in activation and recruitment of many cells that secrete growth factors and modify the ECM, which makes it difficult to address specifically how cardiomyocytes are responding to changes in matrix tension alone. Therefore, we utilized LOX or LOXL overexpression as a tool to stiffen the ECM in the absence of pathophysiologic injury and paracrine factors. Transgenic overexpression of LOX increases myocardial stiffness and results in mild cardiac dysfunction by 9 months of age. While younger adult mice do not display a phenotype at baseline, they have an exaggerated response to pressure overload hypertrophy. In a different set of experiments, adeno-associated viruses (AAV9) for LOXL1, -2, or -3 were administered to mouse pups via cardiac injection at perinatal day 7. By 12 weeks of age, LOXL1 overexpression leads to cardiac hypertrophy with preserved ejection fraction, while increased LOXL2 or LOXL3 results in decreased cardiac function (each with differential patterns of myocardial fibrosis). Ongoing studies are assessing how these functional changes are associated with alterations in tissue stiffness and cardiomyocyte behavior. Determining how cardiomyocytes respond to alterations in the physical properties of the ECM will improve our understanding of the etiology of progressive cardiomyopathies and fibrosis.