The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome.
Ang II type 1a receptor (AT1aR)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). β-Arrestin2 (βarr2) is known to mediate AT1aR-dependent MAPK activation, as well as proproliferative and profibrotic signaling in aortic vascular smooth muscle cells. Therefore, we investigated whether βarr2-dependent signaling contributes to TAA formation in MFS. We used a murine model of MFS [fibrillin (Fbn)(C1039G/+)] to generate an MFS murine model in combination with genetic βarr2 deletion (Fbn(C1039G/+)/βarr2(-/-)). Fbn(C1039G/+)/βarr2(-/-) mice displayed delayed aortic root dilation compared with Fbn(C1039G/+) mice. The mRNA and protein expression of several mediators of TAA formation, including matrix metalloproteinase (MMP)-2 and -9, was reduced in the aorta of Fbn(C1039G/+)/βarr2(-/-) mice relative to Fbn(C1039G/+) mice. Activation of ERK1/2 was also decreased in the aortas of Fbn(C1039G/+)/βarr2(-/-) mice compared with Fbn(C1039G/+) animals. Small interfering RNA targeting βarr2 inhibited angiotensin-stimulated expression of proaneurysmal signaling mediators in primary aortic root smooth muscle cells. Angiotensin-stimulated expression of the proaneurysmal signaling mediators MMP-2 and -9 was inhibited by blockade of ERK1/2 or the EGF receptor, whereas blockade of the transforming growth factor-β receptor had no effect. These results suggest that βarr2 contributes to TAA formation in MFS by regulating ERK1/2-dependent expression of proaneurysmal genes and proteins downstream of the AT1aR. Importantly, this demonstration of the unique signaling mechanism by which βarr2 contributes to aneurysm formation identifies multiple novel, potential therapeutic targets in MFS.
Wisler, JW; Harris, EM; Raisch, M; Mao, L; Kim, J; Rockman, HA; Lefkowitz, RJ
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