The genetic basis of aortic aneurysm

Abstract

Gene identification in human aortic aneurysm conditions is proceeding at a rapid pace and the integration of pathogenesis-based management strategies in clinical practice is an emerging reality. Human genetic alterations causing aneurysm involve diverse gene products including constituents of the extracellular matrix, cell surface receptors, intracellular signaling molecules, and elements of the contractile cytoskeleton. Animal modeling experiments and human genetic discoveries have extensively implicated the transforming growth factor-β (TGF-β) cytokine-signaling cascade in aneurysm progression, but mechanistic links between many gene products remain obscure. This chapter will integrate human genetic alterations associated with aortic aneurysm with current basic research findings in an attempt to form a reconciling if not unifying model for hereditary aortic aneurysm.

Figure 1.

Extracellular matrix: fibrillins, fibulins, and elastin. Vascular smooth muscle cells interact with multiple components of the extracellular matrix including fibrillins, fibulins, and elastin proteins. One function of fibulin proteins is to localize lysyl oxidase (LOX) to fibrillin microfibrils. LOX functions both to catalyze the formation of amorphous elastin from tropoelastin as well as to enzymatically inactivate free TGF-β. As expected, deficiency of either fibulins-4 or fibulins-5 causes a profound failure of elastogenesis. However, only deficiency of fibulin-4 causes aortic aneurysm, perhaps related to its ability to recruit LOX to microfibrils.

Figure 2.

Canonical and noncanonical TGF-β signaling. Microfibrils composed of fibrillin-1 bind and sequester the large latent complex (LLC) of TGF-β. Activation of TGF-β by proteases (e.g., thrombospondin-1) and/or integrin-mediated mechanisms, allows ligand binding to the TGF-β receptor. Canonical TGF-β signaling is mediated by receptor phosphorylation of R-Smads including Smad2 and Smad3. Phosphorylated R-Smads bind to the cosmad, Smad4, and translocate to the nucleus where the complex directs transcriptional events. The TGF-β repressor SKI acts at multiple levels to suppress canonical TGF-β signaling including R-Smad phosphorylation, nuclear translocation, and direct suppression of the transcriptional complex through recruitment of transcriptional corepressors. TGF-β receptors also activate so-called noncanonical signaling such as extracellular regulated kinases or ERKs. TGF-β signaling also activates RhoA activity, a known activator of smooth muscle cell contraction through myosin-actin interaction (green). Human genetic mutations have been described in all depicted members of the canonical TGF-β pathway (blue) but have not been described in noncanonical pathways required for aneurysm progression (red). Mutations causing aneurysm have been described in genes encoding smooth muscle myosin (MYH11), α-smooth muscle actin (ACTA2), and myosin light chain kinase (MYLK) but mechanistic explanation and/or the interaction between these pathways and TGF-β signaling are lacking. β2, TGF-β2; LLC, large latent complex of TGF-β; ROCK, RhoA-kinase; MLCP, myosin light chain phosphatase; MLCK, myosin light chain kinase; α-SMA, α-smooth muscle actin; ERK1, extracellular regulated protein kinase; JNK, c-Jun amino-terminal kinase; MAPK, any MAP kinase: ERK1, JNK, or p38.