Cardiomyocyte-Specific Overexpression of HEXIM1 Prevents Right Ventricular Hypertrophy in Hypoxia-Induced Pulmonary Hypertension in Mice

Noritada Yoshikawa,Toru Satoh,Tomohiro Matsuhashi,Masaharu Kataoka,Akiko Kuribara,Osamu Hosono,Noriaki Shimizu,Motoaki Sano,Keiichi Fukuda,Chikao Morimoto,Hirotoshi Tanaka,Takashi Sawai,Hidenori Ojima,Takako Maruyama,Masataka Kuwana

doi:10.1371/journal.pone.0052522

Abstract

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.

Highlights

Pulmonary arterial hypertension (PAH) occurs in a variety of clinical situations and is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular hypertrophy (RVH) and right ventricular (RV) failure
We found that the eicosanoid vasodilator PGI2 induced Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) protein expression in a dose-dependent manner
To confirm the effect of PGI2 on HEXIM1 protein expression, we studied the cardiac expression of HEXIM1 in PGI synthetase (PGIS)–deficient mice

Summary

Introduction

Pulmonary arterial hypertension (PAH) occurs in a variety of clinical situations and is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular hypertrophy (RVH) and right ventricular (RV) failure. Direct interruption of cardiac remodeling, i.e., cardiac hypertrophy, has been suggested to be beneficial to decrease the risk of heart failure [6,7]. In this line, the PDE-5 inhibitor added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, suggesting that the drugs which have combined effects on both RV and pulmonary artery may be more advantageous than drugs that affect only the pulmonary artery [8,9,10]

Methods

Results

Conclusion