Abstract:
:Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.
journal_name
J Am Heart Assocjournal_title
Journal of the American Heart Associationauthors
West JD,Galindo CL,Kim K,Shin JJ,Atkinson JB,Macias-Perez I,Pavliv L,Knollmann BC,Soslow JH,Markham LW,Carrier EJdoi
10.1161/JAHA.118.011902subject
Has Abstractpub_date
2019-11-05 00:00:00pages
e011902issue
21issn
2047-9980journal_volume
8pub_type
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pub_type: 杂志文章,meta分析,评审
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