UBC Theses and Dissertations
Vascular biology of marfan syndrome : angiotensin II receptors, losartan, and nitric oxide Sellers, Stephanie Leigh
Marfan syndrome (MFS), a connective tissue disorder triggered by mutations in Fibrillin-1, causes life-threatening pathology including aortic aneurysm. Recently, controversy has arisen regarding the use of anti-hypertensive angiotensin-II (AngII) receptor type 1 (ATR1) blocker losartan in MFS as, despite success in animal models, losartan has failed to show superiority over standard β-adrenergic receptor blocker atenolol in preventing or slowing expansion of aortic root aneurysm in MFS patients. Overall, we hypothesized that we could provide new insight into this controversy via development of a novel MFS murine model lacking functional ATR1 signaling. Herein, using this novel model, we demonstrate that MFS aortic, pulmonary and skeletal pathology as well as the therapeutic benefit of losartan in MFS aneurysm prevention are ATR1-independent. Instead, we reveal the primary therapeutic pathway of losartan in MFS to be nitric oxide synthase (NOS)-dependent, as treatment of MFS aneurysm in vivo has no benefit upon inhibition of NOS. Furthermore, losartan is shown to mediate increased NO release in endothelial cells in the absence of AngII and correct NO levels in the plasma of MFS mice. In addition, declining plasma nitric oxide (NO) levels in mice were found to correlate to increasing aortic aneurysm size and sub-analysis of patients treated with losartan shows indices of improved endothelial function to correlate to regression of aortic aneurysm. Finally, we demonstrate the clinical potential of targeting endothelial dysfunction in MFS as murine models of endothelial nitric oxide synthase (eNOS) over-expression and hyper-activation as well as pharmacological activation of endogenous eNOS all result in prevention of MFS aneurysm. Overall, this study is the first to identify key aspects of MFS pathology and treatment including the ATR1-independent nature of MFS aortic, lung, and skeletal pathology and therapeutic benefit of losartan. Moreover, these studies are the first to show a NOS-dependent mechanism of losartan and therapeutic benefit of increasing NO bioavailability and improving endothelial function in MFS. As such, they collectively provide a basis for guiding the evolution of managing and treating MFS as well as future pharmaceutical development.
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