Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy

Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H2O2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an ageassociated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)–induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II–induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II–mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II–induced hypertrophy, which provides novel insights into the role of LOX in cardiac performanceThis work was cofunded by the Spanish Ministerio de Econom´ıa y Competitividad (MINECO)–Instituto de Salud Carlos III (ISCIII) (Grants PI15/01016, SAF2015-64767-R, RD12/0042/0021 and RD12/0042/0053), Fundacio La ´ Marato de TV3 (20152330 and 20153610), and the Fondo ´ Europeo de Desarrollo Regional, a way to build Europe. Centros de Investigacion Biom ´ edica en Red de Enfermedades ´ Cardiovasculares is an initiative of ISCIII. M.G. was supported by the Miguel Servet Program (ISCIII; CP15/00126).Peer reviewe