Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Distribution of lung blood on modified bilateral Glenn shunt evaluated by Tc-99m-MAA lung perfusion scintigraphy: A retrospective study.

The aim of the present study was to determine the distribution of lung blood in a modified bilateral Glenn procedure designed in our institute with lung perfusion scintigraphy. Sixteen consecutive patients who underwent modified bilateral Glenn operation from 2011 to 2014 were enrolled in the study. The control group consisted of 7 patients who underwent bidirectional Glenn shunt. Radionuclide lung perfusion scintigraphy was performed using Tc-99m-macro aggregated albumin (MAA) in all patients. For the patients in modified bilateral Glenn group, the time at which the radioactivity accumulation peaked did not differ significantly between the right and left lung field (t = 0.608, P = 0.554). The incidence of perfusion abnormality in each lung lobe also did not differ significantly (P = 0.426 by Fisher exact test). The radioactive counts were higher in the right lung than in the left lung, but the difference was not statistically significant (t = 1.502, P = 0.157). Radioactive perfusion in the lower lung field was significantly greater than that in the upper field (t = 4.368, P < 0.001). Compared with that in the bidirectional Glenn group, the ratio of radioactivity in the right lung to that in left lung was significantly lower in the modified bilateral Glenn group (t = 3.686, P = 0.002). Lung perfusion scintigraphy confirmed the benefit of the modified bilateral Glenn shunt with regard to more balanced blood perfusion in both lungs.

Nicotine Induces Cardiomyocyte Hypertrophy Through TRPC3-Mediated Ca2+/NFAT Signalling Pathway.

BACKGROUND: Nicotine is thought to be an important risk factor for the development of cardiovascular diseases. However, the effects of nicotine on cardiomyocyte hypertrophy are poorly understood. The present study was designed to explore the role of nicotine in cardiomyocyte hypertrophy and its underlying mechanism. METHODS: We used primary cardiomyocytes isolated from Wistar rats to examine the effects of nicotine on intracellular Ca2+ mobilization and hypertrophy determined by immunofluorescence, quantitative polymerase chain reaction, and western blot analysis. A luciferase reporter assay was used to examine the activity of NFAT signalling. RESULTS: We found that nicotine caused cardiomyocyte hypertrophy, which was accompanied by increased intracellular Ca2+. Nicotine-enhanced intracellular Ca2+ concentration ([Ca2+]i) was significantly abolished by store-operated Ca2+ entry (SOCE) and TRPC inhibitors. Knockdown of TRPC3 significantly decreased nicotine-induced SOCE and hypertrophy. Moreover, calcineurin-nuclear factor of activated T cells (NFAT) is involved in TRPC3-mediated Ca2+ signalling and cardiomyocyte hypertrophy. Notably, upregulation of TRPC3 by nicotine requires TRPC3-mediated Ca2+ influx and calcineurin-NFAT signalling activation. CONCLUSIONS: Our findings demonstrate that the prohypertrophic effect of nicotine on cardiomyocytes is dependent on enhanced TRPC3 expression through a calcium-dependent regulatory loop, which could become a potential target for prevention and treatment of cardiac hypertrophy.