Systolic and diastolic heart failure - Collagen regulation

Left ventricular stiffness and diastolic dysfunction are besides a raise in collagen/matrix also due to an increased crosslinking of the matrix. Lysyloxidases (LOX) are a family of extracellular matrix crosslinking enzymes and critical contributors to the development of cardiac fibrosis. Besides LOX1, particularly LOX-like (LOXL)-2 is an important target since inhibition of LOXL2 has been shown to result in a marked reduction in activated fibroblasts (myofibroblasts), decreased production of cytokines, and decreased TGF-? pathway signaling. Furthermore, higher serum LOXL2 levels have been shown to be associated with increased risk for idiopatic pulmonary fibrosis disease progression. Importantly, LOXL2 is besides the heart expressed in the spleen and the thymus. Given the importance of the cardiosplenic axis in heart failure, linking inflammation with cardiac fibrosis on the one hand, and the expression of LOXL2 in the spleen/thymus and their antifibrotic features on the other hand, a role of LOXL2 in the inflammation and fibrosis process in heart failure is suggested. This project is focused at evaluating the role of LOXL2 in heart failure with preserved ejection fraction (HFpEF). Therefore, cardiac expression of LOXL2 will be evaluated in HFpEF and heart failure with reduced ejection fraction (HFrEF) patients and the effect of LOXL2 on TGF-ß signaling in cardiac fibroblasts from HFpEF and HFrEF patients analyzed. There will be evaluated whether serum LOXL2 levels are a predictive biomarker for cardiac LOXL2 expression and HFpEF, and whether LOXL2 inhibition may abrograte the progression of cardiac fibrosis.