title: Cardiomyocyte-specific overexpression of HEXIM1 prevents right ventricular hypertrophy in hypoxia-induced pulmonary hypertension in mice.
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 I(2), 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.
authors.affiliation: Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Takako
authors.initials: T
authors.lastname: Maruyama
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Toru
authors.initials: T
authors.lastname: Satoh
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ojima
authors.forename: Takashi
authors.initials: T
authors.lastname: Sawai
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuribara
authors.forename: Osamu
authors.initials: O
authors.lastname: Hosono
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D018450:Disease Progression; D019332:Endothelin-1 / Q000097:blood; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications* / Q000209:etiology*; D017380:Hypertrophy, Right Ventricular / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D014157:Transcription Factors
chemical_list: D019332:Endothelin-1; C476123:HEXIM1 protein, human; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D042925:Positive Transcriptional Elongation Factor B