Elucidation of the Pathogenesis of TGF-beta Vasculopathies Identifies Novel Therapeutic Strategies
Doyle, Jefferson James
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Marfan syndrome (MFS) is one of several related disorders that is driven by increased TGFβ signaling. While TGFβ can stimulate both canonical (Smad2/3) and noncanonical (MAPK; ERK, JNK, p38) cascades, this work has identified a novel and critical role for ERK1/2 activation in aortic aneurysm pathogenesis in Marfan mice, while inhibition of ERK1/2 represents a novel therapeutic strategy for the disorder. Angiotensin II influences aortic growth in Marfan mice, but the contribution of its type 1 receptor (AT1R) and type 2 receptor (AT2R) was unknown. This has direct clinical relevance, as the relative therapeutic merits of selective AT1R blockade using losartan versus inhibition of signaling through both receptors using the ACE inhibitor enalapril remained unknown. We find that losartan shows superior efficacy to enalapril in Marfan mice, this is mediated by their differential effects on ERK1/2 activation, and losartan’s full protective effect requires intact AT2R signaling. Calcium channel blockers (CCBs) are used in Marfan patients, although evidence for their efficacy is limited. Surprisingly, we find that CCBs accelerate aortic growth, dissection and premature lethality in Marfan mice, while Marfan patients taking CCBs show increased odds for aortic dissection and need for aortic surgery. CCBs enhance ERK1/2 activation via PKCβ, while PKCβ inhibition using enzastaurin or the clinically available agent hydralazine rescues aortic growth and ERK1/2 activation in Marfan mice, and hence represents a novel therapeutic strategy for the disorder. Finally, we have identified mutations in the proto-oncogene SKI, a repressor of TGFβ, as the cause of Shprintzen Goldberg syndrome, and mutations in TGFB2 ligand as the cause of a Loeys-Dietz like syndrome. We have also found strain-specific differences in aortic aneurysm severity between Marfan mice on C57BL/6J and 129S6 backgrounds, and have identified likely causal genes in QTLs on chromosomes 5 and 11 that link with severe disease, reach genome wide significance, and show additive epistasis. In summary, this work has sought to enhance our understanding of disease pathogenesis in MFS and related conditions, to elucidate a series of novel genetic and pharmacological modifiers of disease progression, and to identify a number of novel therapeutic strategies as a result.