Abstract:
:Nitric oxide (NO) donors are commonly used for the prevention and treatment of ischemic heart disease. Besides their effects on the heart, NO donors may also prevent hypoxic brain damage and exert beneficial effects on atherosclerosis by favoring features of plaque stability. We recently described that apolipoprotein E (ApoE) deficient mice with a mutation in the fibrillin-1 (Fbn1) gene (ApoE-/-Fbn1C1039G+/-) develop accelerated atherosclerosis, plaque rupture, myocardial infarction, cerebral hypoxia and sudden death. In the present study, we evaluated the effects of chronic treatment with the NO donor molsidomine on atherosclerotic plaque stability, cardiac function, neurological symptoms and survival in the ApoE-/-Fbn1C1039G+/- mouse model. Female ApoE-/-Fbn1C1039G+/- mice were fed a Western diet (WD). After 8 weeks of WD, the mice were divided into two groups receiving either molsidomine via the drinking water (1 mg/kg/day; n = 34) or tap water (control; n = 36) until 25 weeks of WD. Survival tended to increase after molsidomine treatment (68% vs. 58% in controls). Importantly, atherosclerotic plaques of molsidomine-treated mice had a thicker fibrous cap (11.1 ± 1.2 vs. 8.1 ± 0.7 μm) and showed an increased occurrence of plaque macrocalcifications (30% vs. 0%), indicative of a more stable phenotype. Molsidomine also improved cardiac function, as fractional shortening was increased (40 ± 2% vs. 27 ± 2%) combined with a decreased end diastolic (3.1 ± 0.2 vs. 3.9 ± 0.2 mm) and end systolic diameter (1.9 ± 0.1 vs. 2.9 ± 0.2 mm). Furthermore, perivascular fibrosis (23 ± 2 vs. 30 ± 2%) and the occurrence of myocardial infarctions (12% vs. 36%) was significantly reduced. Track width, a measure of the animal's hind limb base of support and representative of hypoxic brain damage, was also normalized as a result of molsidomine treatment (2.54 ± 0.04 vs. 2.91 ± 0.09 cm in controls). These findings demonstrate that the NO donor molsidomine improves cardiac function, reduces neurological symptoms and enhances atherosclerotic plaque stability.
journal_name
Vascul Pharmacoljournal_title
Vascular pharmacologyauthors
Roth L,Van der Donckt C,Emini Veseli B,Van Dam D,De Deyn PP,Martinet W,Herman AG,De Meyer GRYdoi
10.1016/j.vph.2019.05.001subject
Has Abstractpub_date
2019-01-01 00:00:00pages
106561eissn
1537-1891issn
1879-3649pii
S1537-1891(19)30028-Xjournal_volume
118-119pub_type
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