MYPT1 reduction is a pathogenic factor of erectile dysfunction.
MYPT1 reduction is a pathogenic factor of erectile dysfunction.
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DOI：
10.1038/s42003-022-03716-y
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发表时间：
2022-07-25
影响因子：
5.9
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中科院分区：
文献类型：
--
作者：
勃起功能障碍（ED）与平滑肌功能障碍密切相关，但其潜在机制尚不完全清楚。我们在这里报道了肌球蛋白磷酸酶靶亚基1 （MYPT1）的表达减少，MYPT1是肌球蛋白轻链磷酸酶的主要调控单位，对血管源性ED的发展至关重要。雄性MYPT1基因敲除小鼠的生育能力降低，阴茎表现出勃起障碍，这可以通过海绵内压（ICP）降低来证明。基因敲除小鼠阴茎平滑肌对g蛋白偶联受体激动作用的反应增强，去极化收缩性和抗性松弛性增强。我们进一步鉴定了一种天然化合物lotusine，它通过抑制SIAH1/2 E3连接酶介导的蛋白降解来增加MYPT1的表达。该化合物充分恢复了Mypt1单倍功能不全小鼠的ICP，改善了阴茎动脉的组织学特征。在糖尿病性ED小鼠（db/db）中，测量了MYPT1表达的降低，并通过lotusine治疗改善了ICP。我们认为MYPT1的减少是血管源性ED的主要致病因素，而lotusine恢复MYPT1可以改善损伤的阴茎平滑肌功能，可能是治疗ED的新策略。肌球蛋白磷酸酶靶亚基1 （MYPT1）的表达降低对血管源性勃起功能障碍的发展至关重要，一种天然化合物lotusine被发现可以增加MYPT1的表达并挽救阴茎平滑肌功能。
Erectile dysfunction (ED) is closely associated with smooth muscle dysfunction, but its underlying mechanisms remains incompletely understood. We here reported that the reduced expression of myosin phosphatase target subunit 1 (MYPT1), the main regulatory unit of myosin light chain phosphatase, was critical for the development of vasculogenic ED. Male MYPT1 knockout mice had reduced fertility and the penises displayed impaired erections as evidenced by reduced intracavernous pressure (ICP). The penile smooth muscles of the knockout mice displayed enhanced response to G-Protein Couple Receptor agonism and depolarization contractility and resistant relaxation. We further identified a natural compound lotusine that increased the MYPT1 expression by inhibiting SIAH1/2 E3 ligases-mediated protein degradation. This compound sufficiently restored the ICP and improved histological characters of the penile artery of Mypt1 haploinsufficiency mice. In diabetic ED mice (db/db), the decreased expression of MYPT1 was measured, and ICP was improved by lotusine treatment. We conclude that the reduction of MYPT1 is the major pathogenic factor of vasculogenic ED. The restoration of MYPT1 by lotusine improved the function of injured penile smooth muscles, and could be a novel strategy for ED therapy. Reduced expression of myosin phosphatase target subunit 1 (MYPT1) is critical for the development of vasculogenic erectile dysfunction and a natural compound, lotusine, is found to increase MYPT1 expression and rescue penile smooth muscle function.
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影响因子：
4.3
作者：
Li W;Sasse KC;Bayguinov Y;Ward SM;Perrino BA
通讯作者：
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DOI：
10.1007/s11626-020-00466-1
发表时间：
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