A novel complex I inhibitor protects against hypertension-induced left ventricular hypertrophy

Since left ventricular hypertrophy (LVH) increases the susceptibility for the development of other cardiac conditions, pharmacotherapy that mitigates pathological cardiac remodeling may prove to be beneficial in patients with LVH. Previous work has shown that the activation of the energy-sensing kinase AMP-activated protein kinase (AMPK) can inhibit some of the molecular mechanisms that are involved in LVH. Of interest, metformin activates AMPK through its inhibition of mitochondrial complex I in the electron transport chain and can prevent LVH induced by pressure overload. However, metformin has additional cellular effects unrelated to AMPK activation, raising questions about whether mitochondrial complex I inhibition is sufficient to reduce LVH. Herein, we characterize the cardiac effects of a novel compound (R118), which is a more potent complex I inhibitor than metformin and is thus used at a much lower concentration. We show that R118 activates AMPK in the cardiomyocyte, inhibits multiple signaling pathways involved in LVH, and prevents G_q protein-coupled receptor agonist-induced prohypertrophic signaling. We also show that in vivo administration of R118 prevents LVH in a mouse model of hypertension, suggesting that R118 can directly modulate the response of the cardiomyocyte to stress. Of importance, we also show that while R118 treatment prevents adaptive remodelling in response to elevated afterload, it does so without compromising systolic function, improves myocardial energetics, and prevents a decline in diastolic function in hypertensive mice. Taken together, our data suggest that inhibition of mitochondrial complex I may be worthy of future investigation for the treatment of LVH.NEW & NOTEWORTHY Inhibition of mitochondrial complex I by R118 reduces left ventricular hypertrophy (LVH) and improves myocardial energetics as well as diastolic function without compromising systolic function. Together, these effects demonstrate the therapeutic potential of complex I inhibitors in the treatment of LVH, even in the presence of persistent hypertension.