Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation.
Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation.
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DOI：
10.1038/s41598-022-08422-7
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发表时间：
2022-04-05
影响因子：
4.6
通讯作者：
Smyth SS
中科院分区：
文献类型：
--
作者：
Van Hoose PM;Yang L;Kraemer M;Ubele M;Morris AJ;Smyth SS
调节脂质磷酸酶3 （LPP3）表达的遗传变异是动脉粥样硬化性心血管疾病发展的危险因素。LPP3在血管炎症的背景下动态上调，特别是在平滑肌细胞（SMC）中的表达升高，然而，LPP3对血管病理的影响尚不完全清楚。我们研究了LPP3和溶解磷脂信号在一个明确定义的病理性主动脉损伤模型中的作用，并观察到血管紧张素II （Ang II）通过核因子κB （NF-κB）信号传导PLPP3全局减少（PLPP3 +/−）或smc特异性缺失（SM22-Δ）增加SMCs中PLPP3的表达，保护高脂血症小鼠免于血管i介导的动脉瘤形成。LPP3表达调节SMC分化状态，降低LPP3水平可促进成纤维细胞样表型。在LPP3缺乏的情况下，生物活性溶血磷脂酸（LPA）失活的减少可能是这些表型的基础，因为LPA受体4的缺失在小鼠中促进了AngII反应的早期主动脉扩张和破裂。LPP3表达和LPA信号影响SMC和血管壁反应，这对主动脉夹层和动脉瘤形成很重要。这些发现可能对正在进行的临床试验中针对LPA代谢和信号传导的治疗具有重要意义。
Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/−) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.
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DOI：
10.1016/j.ejvs.2010.09.011
发表时间：
2011-01-01
影响因子：
5.7
作者：
Moll, F. L.;Powell, J. T.;Rica, J-B
通讯作者：
Rica, J-B
DOI：
10.1161/atvbaha.112.300527
发表时间：
2013-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
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作者：
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通讯作者：
Smyth SS
影响因子：
37.8
作者：
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通讯作者：
Gerszten, Robert E.
影响因子：
20.1
作者：
Hayashi, K;Takahashi, M;Sobue, K
通讯作者：
Sobue, K
影响因子：
4.8
作者：
Pamuklar, Zehra;Federico, Lorenzo;Smyth, Susan S.
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Smyth, Susan S.