BS44 Exploring a novel treatment of cardiac hypertrophy by selectively targeting the ERK1/2 signalling

Background and Aim Cardiac hypertrophy is defined as the enlargement or thickening of the heart muscle. It can be triggered by conditions like high blood pressure, heart disease, or obesity. While hypertrophy may initially be a compensatory mechanism to help the heart pump blood more effectively in response to stressful conditions, prolonged hypertrophy can lead to serious complications, including arrhythmias, heart failure, and sudden cardiac death. The understanding of molecular pathways involved in cardiac hypertrophy, such as ERK1/2 signalling, offers the opportunity to develop novel targeted treatments to slow or reverse the disease. In this study, we explored the protective effects of PD0325901, a highly selective MEK inhibitor (MEKi), in a mouse model of cardiac hypertrophy. Methods Cardiac hypertrophy was induced in eight-week-old male C57BL/6J mice (n=14) by continuous infusion of Angiotensin-II (Ang-II, 1000 ng/kg/min) via subcutaneously implanted osmotic minipumps. After 3 days, mice received either treatment with oral PD0325901 (10 mg/kg/day) (n=7) or the drug vehicle (DMSO) (n=7) for 14 days. Mice not undergoing any procedure were included as control (n=5). At the end of the experimental protocol, mice were euthanised and the hearts harvested for histological analyses. Results Mice receiving Ang-II-Vehicle developed cardiac hypertrophy, as indicated by the thickening of the left ventricular wall (LVW, +1.5-folds vs. control) and enlarged cardiomyocyte cross-sectional area (90 vs. 72 µm2 of control). Moreover, the hearts of vehicle-mice presented increased cardiomyocyte apoptosis and increased homing of proinflammatory CD45+ cells. The MEKi treatment protected against adverse cardiac remodelling. The hearts of PD0325901-treated mice were characterised by reduced LVW thickness and cardiomyocyte cross-sectional area, which were comparable with those of healthy control mice. In addition, MEKi treatment reduced cardiomyocyte apoptosis and the infiltration of CD45+ cells. Interestingly, hearts treated with the MEKi showed enhanced pericyte coverage of capillaries compared with control mice, despite the capillary density remaining unchanged in the three groups. The analysis of myocardial fibrosis is currently ongoing. Conclusions In a mouse model of cardiac hypertrophy, the MEKi treatment, by selectively inhibiting ERK1/2 activity, exerted multiple benefits, including the prevention of LVW and cardiomyocyte remodelling, protection of cardiomyocyte viability, and reduction of the inflammatory cell infiltration. The enhanced pericyte coverage of capillaries in the MEKi group may have improved heart perfusion contributing to the preservation of cardiomyocyte viability. Although more investigation is needed, these data point to MEKi as potential new therapeutics to slow the progression of cardiac hypertrophy.