Mitchell R, Frederick N E, Holzman E R, Agobe F, Allaway H C M, Bagher P
Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Bryan, Texas.
Am J Physiol Heart Circ Physiol. 2021 Jul 1;321(1):H52-H58. doi: 10.1152/ajpheart.00180.2021. Epub 2021 May 28.
Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), an inheritable muscle-wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A/prostanoid receptor (TPr) antagonist ifetroban. Furthermore, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceuticals) is currently recruiting subjects to determine whether ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (∼3-5 mo) and aged (∼9-12 mo) mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619 (U4) was enhanced in young mice versus controls. In addition, young mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mice and both aged and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD. This investigation revealed ) impaired acetylcholine-mediated vasodilation, ) increased U-46619-mediated vasoconstriction, and ) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A/prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mice, a model of Duchenne muscular dystrophy (DMD). Ifetroban has been used in preclinical studies to demonstrate improved cardiac function in mouse models of muscular dystrophy and is currently being investigated in a phase 2 clinical trial in patients with DMD. The current study supports the role of ifetroban in improving coronary artery function in preclinical DMD models, which may contribute to improved cardiovascular health.
扩张型心肌病是杜氏肌营养不良症（DMD）发病和死亡的一个原因，DMD是一种由肌营养不良蛋白基因突变引起的遗传性肌肉萎缩疾病。在肌营养不良小鼠模型中进行的临床前研究表明，口服强效选择性血栓素A/前列腺素受体（TPr）拮抗剂伊非曲班后，心肌病减轻，心脏功能改善。此外，一项2期临床试验（NCT03340675，坎伯兰制药公司）目前正在招募受试者，以确定伊非曲班是否能改善DMD患者的心脏功能。虽然TPr是治疗DMD扩张型心肌病的一个有前景的治疗靶点，但对于通过心脏组织灌注血液的冠状动脉中TPr的功能却知之甚少。在本研究中，使用线肌张力测定法检测了来自年轻（约3 - 5个月）和年老（约9 - 12个月）小鼠（一种广泛使用的DMD小鼠模型）以及年龄匹配对照的离体冠状动脉。与对照组相比，年轻小鼠对浓度增加的TPr激动剂U - 46619（U4）的血管收缩增强。此外，年轻小鼠对浓度增加的毒蕈碱激动剂乙酰胆碱（ACh）的内皮细胞介导的血管舒张有显著减弱。由于年轻小鼠中TPr激活增强，因此在不存在和存在伊非曲班的情况下测量了U4介导的血管收缩。伊非曲班减少了年轻小鼠以及年老小鼠和对照小鼠中U4介导的血管收缩。总体而言，我们的数据表明年轻小鼠中冠状动脉对TPr激活的血管收缩增强，这一表型可用伊非曲班逆转。这些数据对于改善DMD患者的心血管功能可能具有重要的治疗意义。本研究揭示了：）乙酰胆碱介导的血管舒张受损，）U - 46619介导的血管收缩增加，以及）在从年轻小鼠分离的左前降支冠状动脉中，血栓素A/前列腺素受体（TPr）拮抗剂伊非曲班可逆转U - 46619介导的血管收缩增加，年轻小鼠是杜氏肌营养不良症（DMD）的一个模型。伊非曲班已在临床前研究中用于证明在肌营养不良小鼠模型中改善心脏功能，目前正在对DMD患者进行2期临床试验研究。本研究支持伊非曲班在改善临床前DMD模型中冠状动脉功能方面的作用，这可能有助于改善心血管健康。
