Androgens contribute to sex differences in myocardial remodeling under pressure overload by a mechanism involving TGF-β.
Androgens contribute to sex differences in myocardial remodeling under pressure overload by a mechanism involving TGF-β.
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DOI：
10.1371/journal.pone.0035635
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nistal JF
中科院分区：
文献类型：
--
作者：
Montalvo C;Villar AV;Merino D;García R;Ares M;Llano M;Cobo M;Hurlé MA;Nistal JF
在临床研究中，女性主动脉瓣狭窄患者的心肌重塑似乎比男性更有利，即使在绝经后也是如此。在本研究中，我们评估了男性在压力超负荷下循环雄激素是否有助于不利的心肌重塑。我们研究了一岁雄性和雌性小鼠的性别差异。而在这个年龄段的雄性小鼠表现出循环雄激素水平在正常范围内的年轻成年人，循环雌激素在女性减少。在一组同龄去势小鼠中分析了性腺雄激素对心脏重塑的贡献。对动物进行横向主动脉缩窄（TAC）。TAC后2周行超声心动图检查，q-PCR检测心肌TGF-βs、Smads 2和3、胶原、纤维连接蛋白、β-肌球蛋白重链和α-肌球蛋白重链mRNA水平。通过Western Blot进行p-SMAD 2/3的蛋白质检测。用苦味酸天狼星红和Masson三色进行纤维化的组织学染色。与女性相比，男性出现更严重的组织纤维化、左心室扩张和血流动力学功能障碍。TAC-雄性显示出更高的TGF-βs心肌表达水平，并且用TGF-β中和抗体治疗可预防心肌纤维化的发展。睾丸切除术减少了TAC诱导的TGF-βs和TGF-β靶基因的上调，也减少了纤维化和血流动力学功能障碍。雄激素诱导TGF-β表达的能力在暴露于二氢睾酮的NIH-3 T3成纤维细胞和H9 C2心肌细胞中得到证实。我们的研究结果表明，循环雄激素是通过TGF-βs机制导致压力超负荷的老年雄性小鼠心肌中的有害作用的原因。
In clinical studies, myocardial remodeling in aortic valve stenosis appears to be more favorable in women than in men, even after menopause. In the present study, we assessed whether circulating androgens contribute to a less favorable myocardial remodeling under pressure overload in males. We examined sex-related differences in one-year-old male and female mice. Whereas male mice at this age exhibited circulating androgen levels within the normal range for young adults, the circulating estrogens in females were reduced. The contribution of gonadal androgens to cardiac remodeling was analyzed in a group of same-age castrated mice. Animals were subjected to transverse aortic constriction (TAC). Echocardiography was performed 2 weeks after TAC and myocardial mRNA levels of TGF-βs, Smads 2 and 3, collagens, fibronectin, β-myosin heavy chain and α-myosin heavy chain were determined by q-PCR. Protein detection of p-SMAD2/3 was performed by Western Blot. Histological staining of fibrosis was performed with picrosirius red and Masson's trichrome. Compared with females, males developed more severe tissue fibrosis, LV dilation and hemodynamic dysfunction. TAC-males showed higher myocardial expression levels of TGF-βs and the treatment with a neutralizing antibody to TGF-β prevented myocardial fibrosis development. Orchiectomy diminished TAC-induced up-regulation of TGF-βs and TGF-β target genes, and it also reduced fibrosis and hemodynamic dysfunction. The capability of androgens to induce TGF-β expression was confirmed in NIH-3T3 fibroblasts and H9C2 cardiomyocytes exposed to dihydrotestosterone. Our results indicate that circulating androgens are responsible for the detrimental effects in the myocardium of older male mice subjected to pressure overload through a mechanism involving TGF-βs.
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影响因子：
20.1
作者：
Donaldson C;Eder S;Baker C;Aronovitz MJ;Weiss AD;Hall-Porter M;Wang F;Ackerman A;Karas RH;Molkentin JD;Patten RD
通讯作者：
Patten RD
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24
作者：
Hung, Chung-Lieh;Verma, Anil;Solomon, Scott D.
通讯作者：
Solomon, Scott D.
影响因子：
5.8
作者：
KASPERK, C;FITZSIMMONS, R;BAYLINK, D
通讯作者：
BAYLINK, D
影响因子：
8.3
作者：
DESIMONE, G;DEVEREUX, RB;MEYER, RA
通讯作者：
MEYER, RA
影响因子：
37.8
作者：
CARROLL, JD;CARROLL, EP;KARP, RB
通讯作者：
KARP, RB