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  • Title: Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm.
    Author: Zhang P, Hou S, Chen J, Zhang J, Lin F, Ju R, Cheng X, Ma X, Song Y, Zhang Y, Zhu M, Du J, Lan Y, Yang X.
    Journal: Circ Res; 2016 Feb 05; 118(3):388-99. PubMed ID: 26699655.
    Abstract:
    RATIONALE: Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown. OBJECTIVE: To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms. METHODS AND RESULTS: Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs. CONCLUSIONS: The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.
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