Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension.

Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects.

Adolescent nonsuicidal self-injury and cortisol response to the retrieval of adversity: A sibling study.

BACKGROUND: There is evidence for alterations in hypothalamus-pituitary-adrenal (HPA) axis response to the retrieval of traumatic events among individuals with Posttraumatic Stress Disorder. However, no study has so far investigated HPA response to trauma retrieval among individuals engaging in non-suicidal self-injury (NSSI). In the present study, we compared reports of childhood adversity (CA) between adolescents engaging in NSSI and their siblings and tested for differences in the cortisol response to the retrieval of CA. METHODS: The sample consisted of 32 adolescents engaging in NSSI (Mage = 15.8 years) and their siblings (Mage = 15.6 years). Standardized interviews were used for the assessment of CA, NSSI, and axis I diagnoses. Salivary cortisol was measured before and after the trauma interview. Basal HPA axis activity was measured in hair. RESULTS: Reports of CA were moderately interrelated between siblings. Adolescents engaging in NSSI reported more severe CA. A significant decrease of salivary cortisol during the trauma interview was found only in the NSSI group. The NSSI group had significantly higher hair cortisol levels. CONCLUSIONS: Moderate relations in siblings' reports of CA point to non-shared experiences that may play a role in the development of NSSI. In the NSSI group, the decrease of salivary cortisol during the interview may be explained by a downregulation of the HPA axis subsequent to the retrieval of former experience of CA.