In the pathogenesis of Marfan syndrome-associated aortic root aneurysm, mutations in FBN1 (fibrillin-1) lead to aortic disease not just by structural weakness but also through dysregulated cytokine signaling. Which signaling pathway is pathologically activated due to reduced fibrillin-1 sequestration of the cytokine precursor?

• A TGF-beta signaling is pathologically upregulated because fibrillin-1 normally sequesters latent TGF-beta complex (LTBP) in the ECM; FBN1 loss increases free TGF-beta causing smooth muscle cell apoptosis and MMP upregulation ✓
• B FGF-2 signaling is activated, driving endothelial-to-mesenchymal transition in the aortic media
• C IL-6/JAK-STAT pathway is activated by released biglycan fragments from disrupted elastic lamella
• D Angiotensin II/AT1R signaling is primarily activated through fibrillin-1 direct receptor binding, not TGF-beta

Explanation

Fibrillin-1 is a structural component of microfibrils that physically sequesters latent TGF-beta complexes (via LTBP-1 binding) in the ECM, keeping TGF-beta inactive. In Marfan syndrome, reduced or dysfunctional fibrillin-1 releases sequestered latent TGF-beta, leading to pathologically elevated TGF-beta signaling in the aortic wall. This activates SMAD2/3 pathways driving smooth muscle cell apoptosis, MMP-2/9 upregulation (elastic lamella degradation), and myofibroblast activation, collectively mediating aortic root dilation and dissection. This TGF-beta mechanism forms the rationale for losartan (AT1R antagonist) therapy in Marfan — losartan reduces TGF-beta signaling via AT1R-Smad2/3 crosstalk.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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