Cardiomyocyte-specific overexpression of HEXIM1 prevents right ventricular hypertrophy in hypoxia-induced pulmonary hypertension in mice.
Cardiomyocyte-specific overexpression of HEXIM1 prevents right ventricular hypertrophy in hypoxia-induced pulmonary hypertension in mice.
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DOI：
10.1371/journal.pone.0052522
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tanaka H
中科院分区：
文献类型：
--
作者：
Yoshikawa N;Shimizu N;Maruyama T;Sano M;Matsuhashi T;Fukuda K;Kataoka M;Satoh T;Ojima H;Sawai T;Morimoto C;Kuribara A;Hosono O;Tanaka H
右心室肥大（RVH）和右心室（RV）收缩功能障碍是肺动脉高压（PAH）预后的主要决定因素，PAH仍然是一种严重疾病。最近，直接中断左心室肥厚被认为可以降低左心衰的风险。六亚甲基双乙酰胺诱导蛋白1（HEXIM 1）是正转录延伸因子B（P-TEF B）的负调节因子，其激活RNA聚合酶II（RNAP II）依赖性转录，并且其激活与左心室肥大强烈相关。我们推测，在PAH的进展过程中，增加的P-TEFb活性也可能在RVH中发挥作用，HEXIM 1可能对这种过程具有预防作用。我们发现，在小鼠心脏中，HEXIM 1在出生后早期高度表达，其表达逐渐减少，而PAH治疗药物前列腺素I2可增加心肌细胞中的HEXIM 1水平。提示HEXIM 1可能对RV心肌细胞的生长具有负性影响，并参与RV心肌细胞的调控。使用腺病毒介导的基因传递到培养的大鼠心肌细胞，我们发现，过度表达HEXIM 1防止内皮素-1诱导的磷酸化RNAPII，心肌细胞肥大，肥大基因的mRNA表达，而缺乏中央碱性区域，减少P-TEFb抑制活性的HEXIM 1突变体，不能。此外，我们建立了心肌细胞特异性HEXIM 1转基因小鼠，并揭示了HEXIM 1改善RVH并防止缺氧诱导的PAH模型中的RV扩张。总之，这些发现表明，心肌细胞特异性过表达HEXIM 1抑制慢性缺氧下向RVH的进展，最可能是通过抑制P-TEFb介导的心肌细胞增大。我们的结论是P-TEFb/HEXIM 1依赖性转录调控可能在RVH中发挥病理生理作用，并成为减轻PAH中RVH的新治疗靶点。
Right ventricular hypertrophy (RVH) and right ventricular (RV) contractile dysfunction are major determinants of prognosis in pulmonary arterial hypertension (PAH) and PAH remains a severe disease. Recently, direct interruption of left ventricular hypertrophy has been suggested to decrease the risk of left-sided heart failure. Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is a negative regulator of positive transcription elongation factor b (P-TEFb), which activates RNA polymerase II (RNAPII)-dependent transcription and whose activation is strongly associated with left ventricular hypertrophy. We hypothesized that during the progression of PAH, increased P-TEFb activity might also play a role in RVH, and that HEXIM1 might have a preventive role against such process. We revealed that, in the mouse heart, HEXIM1 is highly expressed in the early postnatal period and its expression is gradually decreased, and that prostaglandin I2, a therapeutic drug for PAH, increases HEXIM1 levels in cardiomyocytes. These results suggest that HEXIM1 might possess negative effect on cardiomyocyte growth and take part in cardiomyocyte regulation in RV. Using adenovirus-mediated gene delivery to cultured rat cardiomyocytes, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced phosphorylation of RNAPII, cardiomyocyte hypertrophy, and mRNA expression of hypertrophic genes, whereas a HEXIM1 mutant lacking central basic region, which diminishes P-TEFb-suppressing activity, could not. Moreover, we created cardiomyocyte-specific HEXIM1 transgenic mice and revealed that HEXIM1 ameliorates RVH and prevents RV dilatation in hypoxia-induced PAH model. Taken together, these findings indicate that cardiomyocyte-specific overexpression of HEXIM1 inhibits progression to RVH under chronic hypoxia, most possibly via inhibition of P-TEFb-mediated enlargement of cardiomyocytes. We conclude that P-TEFb/HEXIM1-dependent transcriptional regulation may play a pathophysiological role in RVH and be a novel therapeutic target for mitigating RVH in PAH.
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影响因子：
20.1
作者：
Espinoza-Derout J;Wagner M;Salciccioli L;Lazar JM;Bhaduri S;Mascareno E;Chaqour B;Siddiqui MA
通讯作者：
Siddiqui MA
影响因子：
3.5
作者：
Huang, FC;Wagner, M;Siddiqui, MAQ
通讯作者：
Siddiqui, MAQ
DOI：
10.1111/j.1582-4934.2008.00404.x
发表时间：
2009-08-01
影响因子：
5.3
作者：
Mascareno, Eduardo;Manukyan, Irena;Siddiqui, M. A. Q.
通讯作者：
Siddiqui, M. A. Q.
影响因子：
1.2
作者：
Kusuhara, M;Nagasaki, K;Yamaguchi, K
通讯作者：
Yamaguchi, K
DOI：
10.1164/rccm.200703-349oc
发表时间：
2008-01-15
影响因子：
24.7
作者：
Obata, Hiroaki;Sakai, Yoshiki;Nagaya, Noritoshi
通讯作者：
Nagaya, Noritoshi