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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase.
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Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase.

机译：通过腺苷酸环化酶的活化和过表达抑制心肌成纤维细胞的形成和胶原蛋白的合成。

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摘要

Transformation of fibroblasts to myofibroblasts, characterized by expression of alpha-smooth muscle actin (alpha-SMA) and production of extracellular matrix (ECM) components, is a key event in connective tissue remodeling. Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by cardiac fibroblasts (CFs) causes fibrosis, myocardial stiffening, and cardiac dysfunction. We tested whether adenylyl cyclase (AC) activation (increased cAMP levels) modulates the transformation of adult rat CF to myofibroblasts, as assessed by immunofluorescent microscopy, immunoblotting, and collagen synthesis. A 24-h incubation of CF with TGF-beta or angiotensin II increased alpha-SMA expression, which was inhibited by the AC agonist forskolin and a cAMP analog that activates protein kinase A. Treatment with forskolin blunted serum-, TGF-beta-, and angiotensin II-stimulated collagen synthesis. CFs engineered to overexpress type 6 AC had enhanced forskolin-promoted cAMP formation, greater inhibition by forskolin of TGF-beta-stimulated alpha-SMA expression, and a decrease in the EC(50) of forskolin to reduce serum-stimulated collagen synthesis. The AC stimulatory agonist adrenomedullin inhibited collagen synthesis in CF that overexpressed AC6 but not in controls. Thus, AC stimulation blunts collagen synthesis and, in parallel, the transformation of adult rat CF to myofibroblasts. AC overexpression enhances these effects, "uncovering" an inhibition by adrenomedullin. These findings implicate cAMP as an inhibitor of ECM formation by means of blockade of the transformation of CF to myofibroblasts and suggest that increasing AC expression, thereby enhancing cAMP generation through stimulation of receptors expressed on CF, could provide a means to attenuate and prevent cardiac fibrosis and its sequelae.
机译：成纤维细胞向成肌纤维细胞的转化，以表达α-平滑肌肌动蛋白（alpha-SMA）和产生细胞外基质（ECM）成分为特征，是结缔组织重塑中的关键事件。在心脏等组织中需要抑制这种转化的方法，在这些组织中，心脏成纤维细胞（CF）产生的过多ECM会导致纤维化，心肌变硬和心脏功能障碍。通过免疫荧光显微镜，免疫印迹和胶原蛋白合成评估，我们测试了腺苷酸环化酶（AC）活化（cAMP水平升高）是否调节成年大鼠CF向成纤维细胞的转化。 CF与TGF-β或血管紧张素II孵育24小时可增加α-SMA的表达，这被AC激动剂毛喉素和激活蛋白激酶A的cAMP类似物抑制。用毛喉素处理会使钝化的血清TGF-β，和血管紧张素II刺激的胶原蛋白合成。被设计为过表达6 AC的CFs增强了福司可林促进的cAMP的形成，福司可林对TGF-β刺激的α-SMA表达的抑制作用更大，并且福司可林的EC（50）降低，从而降低了血清刺激的胶原合成。 AC刺激性激动剂肾上腺髓质素抑制过表达AC6的CF中的胶原蛋白合成，但在对照组中则没有。因此，AC刺激会钝化胶原蛋白的合成，并同时抑制成年大鼠CF向成纤维细胞的转化。 AC过表达增强了这些作用，“揭示”了肾上腺髓质素的抑制作用。这些发现暗示cAMP通过阻止CF向成纤维细胞的转化而成为ECM形成的抑制剂，并表明增加AC表达，从而通过刺激CF上表达的受体来增强cAMP产生，可以提供减轻和预防心脏纤维化的手段。及其后遗症。

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