Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation

摘要

Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy with variable muscular dystrophy. These mutations enhance mitogen-activated protein kinase signaling in the heart and pharmacological inhibition of extracellular signal-regulated kinase (ERK) 1 and 2 improves cardiac function in LmnaH222P/H222P mice. In the current study, we crossed mice lacking ERK1 to LmnaH222P/H222P mice and examined cardiac performanceandsurvival.MaleLmnaH222P/H222P/Erk1-/-micelackingERK1hadsmaller leftventricularend systolic diameters and increased fractional shortening (FS) at 16 weeks of age than LmnaH222P/H222P/Erk1+/+ mice. Their mean survival was also significantly longer. However, the improved cardiac function was abrogated at 20 weeks of age concurrent withan increased activity ofERK2.LmnaH222P/H222P/Erk1-/- mice treatedwithan inhibitor of ERK1/2 activation had smaller left ventricular diameters and increased FS at 20 weeks of age. These results provide genetic evidence that ERK1 and ERK2 contribute to the development of cardiomyopathy caused by LMNA mutations and reveal interplay between these isoenzymes in maintaining a combined pathological activity inheart.