Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is increasingly diagnosed in elderly patients who also have an increased risk of co-morbid atherosclerosis. Apolipoprotein E-deficient (ApoE−/−) mice develop atherosclerosis with severe PAH when fed a high-fat diet (HFD) and have increased levels of endothelin (ET)-1. ET-1 receptor antagonists (ERAs) are used for the treatment of PAH but less is known about whether ERAs are beneficial in atherosclerosis. We therefore examined whether treatment of HFD-ApoE−/− mice with macitentan, a dual ETA/ETB receptor antagonist, would have any effect on both atherosclerosis and PAH. ApoE−/− mice were fed chow or HFD for eight weeks. After four weeks of HFD, mice were randomized to a four-week treatment of macitentan by food (30 mg/kg/day dual ETA/ETB antagonist), or placebo groups. Echocardiography and closed-chest right heart catheterization were used to determine PAH phenotype and serum samples were collected for cytokine analysis. Thoracic aortas were harvested to assess vascular reactivity using wire myography, and histological analyses were performed on the brachiocephalic artery and aortic root to assess atherosclerotic burden. Macitentan treatment of HFD-fed ApoE−/− mice was associated with a beneficial effect on the PAH phenotype and led to an increase in endothelial-dependent relaxation in thoracic aortae. Macitentan treatment was also associated with a significant reduction in interleukin 6 (IL-6) concentration but there was no significant effect on atherosclerotic burden. Dual blockade of ETA/ETB receptors improves endothelial function and improves experimental PAH but had no significant effect on atherosclerosis.
Highlights
Idiopathic pulmonary arterial hypertension (IPAH) is a devastating life-shortening condition.[1]
Macitentan improves cardiac hemodynamics associated with PAH phenotype in highfat diet (HFD)-fed ApoEÀ/À mice
As previously reported,[16,36] there was no significant increase in Right ventricular (RV) hypertrophy (RVH) in HFD-fed ApoEÀ/À mice, and there were no significant differences in macitentan-treated HFDfed ApoEÀ/À mice when compared with treatment-naıve ApoEÀ/À mice
Summary
Idiopathic pulmonary arterial hypertension (IPAH) is a devastating life-shortening condition.[1] often thought to predominantly affect young women, recent data from the European COMPERA study highlights the increasing number of elderly patients aged >65 years diagnosed with IPAH.[2] Atherosclerosis and atheroscleroticassociated diseases are the leading cause of cardiovascular disease and death worldwide.[3,4] There are multiple risk factors for atherosclerosis, including genetics, high levels of C-reactive protein, and diet, but the impact of more traditional risk factors such as high levels of triglyceride and LDL cholesterol, smoking, and age still remains significant.[5,6] Pro-inflammatory cytokines, such as those from the interleukin (IL) family, are upregulated in both.
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