Enhanced hypertrophy in ob/ob mice due to an impairment in expression of atrial natriuretic peptide.
Enhanced hypertrophy in ob/ob mice due to an impairment in expression of atrial natriuretic peptide.
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DOI：
10.1016/j.vph.2009.06.005
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发表时间：
2009-08
影响因子：
4
通讯作者：
Siddiqui, M. A. Q.
中科院分区：
文献类型：
--
作者：
Mascareno, Eduardo;Beckles, Daniel;Dhar-Mascareno, Manya;Siddiqui, M. A. Q.
我们研究了在压力超负荷导致的左心室肥厚（LVH）发展过程中，瘦素信号转导发挥作用的分子机制。为此，对ob/ob瘦素缺陷型和C57 BL/6 J对照小鼠进行横向主动脉缩窄（TAC）。对照假手术C57 BL/6 J和ob/ob小鼠、沿着C57 BL/6 J和ob/ob瘦素缺陷小鼠经受横向主动脉收缩（TAC）15天，然后评价与压力超负荷肥大相关的形态学、生理学和分子变化。通过超声心动图评估显示，与C57 BL/6 J相比，经受横向主动脉缩窄（TAC）的ob/ob小鼠的左心室质量（LVmass）和室壁厚度显著增加。左室肥厚分子标志物如心钠素（ANP）的表达分析显示，与C57 BL/6 J小鼠相比，ob/ob小鼠的ANP水平增加平缓。我们观察到瘦素在调节ANP基因启动子的转录活性中起作用。瘦素通过调节心肌细胞中核因子激活T细胞（NFAT）家族转录因子的成员NFATc 4起作用。我们的体内研究表明，ob/ob小鼠接受TAC未能激活心脏中的NFATc 4，然而，腹腔注射瘦素在ob/ob小鼠中恢复NFATc 4 DNA结合活性并诱导ANP基因的表达。本研究确立了瘦素在压力超负荷肥大过程中作为抗肥大剂的作用，并表明一个关键的分子事件是瘦素介导的NFATc 4的激活，其调节ANP基因启动子的转录激活。
We investigated the molecular mechanism(s) that play a role in leptin signaling during the development of left ventricular hypertrophy (LVH) due to pressure overload. To this end, ob/ob leptin deficient and C57BL/6J control mice were subjected transverse aortic constriction (TAC). Control sham C57BL/6J and ob/ob mice, along with C57BL/6J and ob/ob leptin deficient mice were subjected transverse aortic constriction (TAC) for 15 days and then evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy. Evaluation by echocardiography revealed a significant increase in left ventricular mass (LVmass) and wall thickness in ob/ob mice subjected to transverse aortic constriction (TAC) as compared to C57BL/6J. Analysis of the expression of molecular markers of LVH, such as atrial natriuretic peptide (ANP), revealed a blunted increase in the level of ANP in ob/ob mice as compared to C57BL/6J mice. We observed that leptin plays a role in modulating the transcriptional activity of the promoter of the ANP gene. Leptin acts by regulating NFATc4, a member of the nuclear factor activated T cell (NFAT) family of transcription factors in cardiomyocytes. Our in vivo studies revealed that ob/ob mice subjected to TAC failed to activate the NFATc4 in the heart, however, intraperitoneal injection of leptin in ob/ob mice restored the NFATc4 DNA-binding activity and induced expression of the ANP gene. This study establishes the role of leptin as an anti-hypertrophic agent during pressure overload hypertrophy, and suggests that a key molecular event is the leptin mediated activation of NFATc4 that regulates the transcriptional activation of the ANP gene promoter.
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DOI：
10.1073/pnas.94.26.14730
发表时间：
1997-12-23
影响因子：
11.1
作者：
Oliver, PM;Fox, JE;Maeda, N
通讯作者：
Maeda, N
影响因子：
4.3
作者：
Trivedi, Premal;Yang, Ronghua;Barouch, Lili A.
通讯作者：
Barouch, Lili A.
影响因子：
4.8
作者：
Christoffersen, C;Bollano, E;Nielsen, LB
通讯作者：
Nielsen, LB
影响因子：
5.8
作者：
Perego, L;Pizzocri, P;Pontiroli, AE
通讯作者：
Pontiroli, AE
影响因子：
4
作者：
Mascareno, E;Beckles, DL;Siddiqui, MAQ
通讯作者：
Siddiqui, MAQ