Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females.
Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females.
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DOI：
10.1186/1465-9921-12-159
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发表时间：
2011-12-20
影响因子：
5.8
通讯作者：
Maclean MR
中科院分区：
文献类型：
--
作者：
Dempsie Y;Nilsen M;White K;Mair KM;Loughlin L;Ambartsumian N;Rabinovitch M;Maclean MR
特发性和家族性肺动脉高压（PAH）在女性中比男性更常见。然而，其原因尚不清楚。钙结合蛋白S100A4/Mts1 （Mts1）及其内源性受体（晚期糖基化终产物受体；RAGE）都与PAH的发生有关。我们希望研究Mts1/RAGE通路是否在与多环芳烃相关的性别偏见中发挥作用。我们通过测量肺动脉重塑、右心室收缩压（sRVP）和右心室肥厚（RVH），研究性别对Mts1过表达小鼠（Mts1+小鼠）PAH发展的影响。采用qRT-PCR和免疫组化检测肺动脉Mts1和RAGE表达的性别差异。采用Western blotting和细胞计数法研究17β-雌二醇、Mts1和RAGE对人肺动脉平滑肌细胞（hPASMCs）增殖的相互作用。统计分析酌情采用Dunnetts后验单方差分析或Bonferronis后验双方差分析。雌性Mts1+小鼠出现sRVP增加和肺血管重构，而雄性Mts1+小鼠未受影响。Mts1+小鼠丛状病变的发展是雌性特有的。这些病变内皮和外皮层的Mts1和RAGE均呈阳性。肺动脉Mts1在雌性小鼠中的表达高于雄性小鼠，并定位于非丛状样肺动脉的内侧和外皮层。RAGE基因表达和免疫反应性在雄性和雌性Mts1+小鼠中相似，RAGE染色定位于邻近气道的非丛状肺动脉内皮层。在与气道无关的非丛状肺动脉中，RAGE染色出现在内侧和外皮层。17β-雌二醇的生理浓度增加了hPASMCs中Mts1的表达。17β-雌二醇诱导的hPASMC增殖可被可溶性RAGE抑制，而可溶性RAGE可拮抗RAGE的膜结合形式。Mts1过表达与雌性结合，有利于小鼠实验性PAH的发生。Mts1的上调和随后RAGE的激活可能有助于17β-雌二醇诱导的hPASMCs增殖。
Idiopathic and familial forms of pulmonary arterial hypertension (PAH) occur more frequently in women than men. However, the reason for this remains unknown. Both the calcium binding protein S100A4/Mts1 (Mts1) and its endogenous receptor (receptor for advanced glycosylation end products; RAGE) have been implicated in the development of PAH. We wished to investigate if the Mts1/RAGE pathway may play a role in the gender bias associated with PAH. We investigated the effects of gender on development of PAH in mice over-expressing Mts1 (Mts1+ mice) via measurement of pulmonary arterial remodeling, systolic right ventricular pressure (sRVP) and right ventricular hypertrophy (RVH). Gender differences in pulmonary arterial Mts1 and RAGE expression were assessed by qRT-PCR and immunohistochemistry. Western blotting and cell counts were used to investigate interactions between 17β-estradiol, Mts1 and RAGE on proliferation of human pulmonary artery smooth muscle cells (hPASMCs). Statistical analysis was by one-way analysis of variance with Dunnetts post test or two-way analysis of variance with Bonferronis post test, as appropriate. Female Mts1+ mice developed increased sRVP and pulmonary vascular remodeling, whereas male Mts1+ mice remained unaffected. The development of plexiform-like lesions in Mts1+ mice was specific to females. These lesions stained positive for both Mts1 and RAGE in the endothelial and adventitial layers. Expression of pulmonary arterial Mts1 was greater in female than male Mts1+ mice, and was localised to the medial and adventitial layers in non plexiform-like pulmonary arteries. RAGE gene expression and immunoreactivity were similar between male and female Mts1+ mice and RAGE staining was localised to the endothelial layer in non plexiform-like pulmonary arteries adjacent to airways. In non-plexiform like pulmonary arteries not associated with airways RAGE staining was present in the medial and adventitial layers. Physiological concentrations of 17β-estradiol increased Mts1 expression in hPASMCs. 17β-estradiol-induced hPASMC proliferation was inhibited by soluble RAGE, which antagonises the membrane bound form of RAGE. Mts1 over-expression combined with female gender is permissive to the development of experimental PAH in mice. Up-regulation of Mts1 and subsequent activation of RAGE may contribute to 17β-estradiol-induced proliferation of hPASMCs.
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影响因子：
15.9
作者：
Hansmann, Georg;de Jesus Perez, Vinicio A.;Rabinovitch, Marlene
通讯作者：
Rabinovitch, Marlene
影响因子：
37.8
作者：
Dempsie, Yvonne;Morecroft, Ian;MacLean, Margaret R.
通讯作者：
MacLean, Margaret R.
DOI：
10.1183/09031936.00010409
发表时间：
2009-11
期刊：
The European respiratory journal
影响因子：
--
作者：
Austin ED;Cogan JD;West JD;Hedges LK;Hamid R;Dawson EP;Wheeler LA;Parl FF;Loyd JE;Phillips JA 3rd
通讯作者：
Phillips JA 3rd
影响因子：
37.8
作者：
MacLean, MR;Deuchar, GA;Harmar, A
通讯作者：
Harmar, A
影响因子：
20.1
作者：
Spiekerkoetter E;Guignabert C;de Jesus Perez V;Alastalo TP;Powers JM;Wang L;Lawrie A;Ambartsumian N;Schmidt AM;Berryman M;Ashley RH;Rabinovitch M
通讯作者：
Rabinovitch M