Antagonism of the Thromboxane‐Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy

Autor: John Jonghyun Shin, Kyungsoo Kim, James West, Bjorn C. Knollmann, James B. Atkinson, Leo Pavliv, Jonathan H. Soslow, Cristi L. Galindo, Larry W. Markham, Ines Macias-Perez, Erica J. Carrier
Rok vydání: 2019
Předmět:
Male
Thromboxane
Receptors
Thromboxane
Cardiomyopathy
Early death
030204 cardiovascular system & hematology
Mice
Random Allocation
chemistry.chemical_compound
0302 clinical medicine
Pediatric Cardiology
Medicine
Muscular dystrophy
Receptor
Oxazoles
Original Research
Mice
Knockout
0303 health sciences
musculoskeletal system
3. Good health
TC receptor
Cardiology
Female
Cardiomyopathies
Cardiology and Cardiovascular Medicine
musculoskeletal diseases
medicine.medical_specialty
Prostaglandin Antagonists
receptor blocker
03 medical and health sciences
Internal medicine
Animals
030304 developmental biology
Heart Failure
Pharmacology
business.industry
Prostanoid
Bridged Bicyclo Compounds
Heterocyclic
medicine.disease
Fibrosis
Muscular Dystrophy
Duchenne
Disease Models
Animal
Animal Models of Human Disease
chemistry
Heart failure
Mice
Inbred mdx
Duchenne muscular dystrophy cardiomyopathy
business
Antagonism
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Muscular dystrophy ( MD ) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane‐prostanoid receptor ( TP r) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TP r activation contributes to the cardiac phenotype of MD , and that TP r 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 TP r 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. TP r 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 TP r antagonism, which also normalized cardiac expression of claudin‐5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TP r antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb‐girdle MD . Based on these studies, ifetroban and other TP r antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD .
Databáze: OpenAIRE
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