Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation |
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Authors: | Antoine Muchir Wei Wu Fusako Sera Shunichi Homma Howard J Worman |
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Institution: | 1. Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA;2. Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA |
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Abstract: | BackgroundMutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of LmnaH222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in LmnaH222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit.MethodsMale LmnaH222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated.ResultsTreatment of LmnaH222P/H222P mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20 weeks of age.ConclusionsBoth ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in LmnaH222P/H222P mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations. |
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Keywords: | Lamin Cardiomyopathy Nuclear envelope Mitogen-activated protein kinase |
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