Accelerated Marfan syndrome model recapitulates established signaling pathways.
OBJECTIVE: Marfan syndrome (MFS) represents a genetic disorder with a range of clinical features, including proximal aortic aneurysms. Extensive research has revealed an abundance of transforming growth factor beta from a mutation in fibrillin-1 to be the key biochemical mechanism of aneurysm formation. Many important signaling pathways downstream of transforming growth factor beta have been further characterized. Our laboratory has previously demonstrated a unique murine model of MFS resulting in the accelerated formation of ascending aortic aneurysms and dilated cardiomyopathies. This study aims to characterize the relevance of this model to known signaling mechanisms in MFS. METHODS: Fibrillin 1C1039G/+ heterozygous mice (ie, MFS), with a mutation in fibrillin-1, were supplemented with 4.5 mg/kg/d angiotensin II to accelerate aneurysm formation. Four mouse groups were analyzed: wild type with or without angiotensin II and MFS with or without angiotensin II. Aortic tissue from these samples were subjected to western blotting and phosphoimaging to query various signaling pathways. RESULTS: Mice with MFS displayed downstream regulation in both the canonical (Smad2) and noncononical (extracellular signal-regulated kinases and P38) pathways characteristic of MFS. However, these downstream signals were exaggerated in the MFS mice supplemented with angiotensin II (accelerated model), matching the observed phenotypic severity of this model. CONCLUSIONS: The murine MFS model depicted here accelerates ascending aortic aneurysm formation and cardiomyopathies via well-characterized MFS signaling cascades. The mechanistic relevance of the accelerated murine MFS model suggests that it could be an important tool in future studies hoping to characterize MFS signaling in an expedited experimental design.
Gensicke, NM; Cavanaugh, NB; Andersen, ND; Huang, T; Qian, L; Dyle, MC; Turek, JW
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