ERK Activation Unifies Deleterious Gene-by-Gene and Gene-by-Environment Interactions in Marfan Syndrome. J. J. Doyle1,2, A. J. Doyle*1, N. Wilson1, D. Bedja3, J. Pardo-Habashi1,4, L. Myers1, K. Braunstein5, N. Huso1, S. Bachir1, O. Squires1, B. Rusholme1, A. George1, M. Lindsay1, D. Huso3, C. Thomas6, D. Judge7, H. C. Dietz1,7,8 1) Inst Gen Med, Johns Hopkins, Baltimore, MD; 2) Good Samaritan Hospital, Baltimore, MD; 3) Dept of Pathobiology, Johns Hopkins, Baltimore, MD; 4) Dept of Pediatrics, Johns Hopkins, Baltimore, MD; 5) Dept of Pathology, Johns Hopkins, Baltimore, MD; 6) National Institutes of Health Chemical Genomics Center, Rockville, MD; 7) Dept of Medicine, Johns Hopkins, Baltimore, MD; 8) Howard Hughes Medical Institute, Baltimore, MD.

   Many of the manifestations of Marfan syndrome (MFS), including aortic aneurysm, associate with a clear signature of increased TGF signaling and can be attenuated by TGF neutralizing antibody or the AT1R blocker losartan. While TGF can signal through both canonical (Smad2/3) and noncanonical (ERK) pathways, selective ERK inhibition using RDEA119 fully rescues aortic aneurysm growth in MFS mice. To further inform our understanding of ERK activation in MFS, we analyzed its role in mediating both genetic and environmental modifications of aortic disease in MFS mice. Compared to MFS mice on a pure BL6 background, MFS mice on a pure 129 background show a 4-fold increase in aortic aneurysm growth and unique lethality from aortic dissection. Calcium channel blockers (CCBs) are used in MFS patients due to their antihypertensive effects, despite limited empirical evidence for their utility. Unexpectedly, we find that BL6 MFS mice treated with the CCBs amlodipine or verapamil show hyperacute aneurysm expansion, aortic rupture and premature lethality. Compared to BL6 animals, 129 MFS mice show an overt increase in Smad2/3 and ERK activation, as do CCB-treated MFS mice compared to placebo-treated littermates. Despite the severity of these provocations, both losartan and RDEA119 fully rescue aortic aneurysm growth in 129 MFS mice, while dual treatment with CCB and either losartan or RDEA119 fully rescues this deleterious gene-by-environment interaction. Taken together, these data instill confidence that these conditional experimental provocations inform the underlying pathogenesis of MFS. We next sought to identify a central nodal point that integrates these observations. AT1R, TGF and CCBs are known to drive IP3-mediated PKC activation, a critical mediator of ERK activation, while AT2R signaling (which is protective in MFS) can antagonize it. MFS mice show greatly increased PKC activation compared to WT animals, which is further enhanced by either the 129 background or CCB therapy. Furthermore, hydralazine (which can inhibit IP3-mediated PKC activation) fully rescues aortic aneurysm growth in MFS mice, in conjunction with reduced PKC and ERK activation. These data definitively implicate ERK in driving aortic disease in MFS mice, implicate PKC as a critical integration point in the pathway, challenge prevailing assumptions about the effect of CCBs in MFS, and provide rationale and incentive for a clinical trial of ERK and PKC antagonists and hydralazine in MFS.

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