Zhan Yin

BACKGROUND: A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB). METHODS AND RESULTS: Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, alpha-tubulin, beta-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition. CONCLUSIONS: These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.

Cited2 is a cAMP-responsive element-binding protein (CBP)/p300 interacting transcriptional modulator and a proposed negative regulator for hypoxia-inducible factor (HIF)-1alpha through its competitive binding with HIF-1alpha to CBP/p300. Disruption of the gene encoding Cited2 is embryonic lethal because of defects in the development of heart and neural tube. Morphological and Doppler echocardiographic analyses of Cited2(-/-) embryos reveal severe cardiovascular abnormalities, including pulmonic arterial stenosis and ventricular septal defects accompanied by high peak outflow velocities, features of the human congenital cardiac defect termed tetralogy of Fallot. The mRNA levels of several HIF-1alpha-responsive genes, such as vascular endothelial growth factor (VEGF), Glut1, and phosphoglycerate kinase 1, increased in the Cited2(-/-) hearts. The increase of VEGF levels is significant, because defects in the Cited2(-/-) embryos closely resemble the major defects observed in the VEGF transgenic embryos. Finally, compared with wild-type, cultured fibroblasts from Cited2(-/-) embryos demonstrate an enhanced expression of HIF-1alpha-responsive genes under hypoxic conditions. These observations suggest that functional loss of Cited2 is responsible for defects in heart and neural tube development, in part because of the modulation of HIF-1 transcriptional activities in the absence of Cited2. These findings demonstrate that Cited2 is an indispensable regulatory gene during prenatal development.

during lipid metabolism occurs through the regulation of Pgc1a for mitochondrial biogenesis and oxidative metabolism within zebrafish VAT.

Cytochrome P450 (Cyp)17A1 has both 17a-hydroxylase and 17,20-lyase activities, which are involved in the steroidogenic pathway that produces androgens and estrogens. Previously, a phenotype of all-male cyp17a1-deficient zebrafish generated by transcription activatorlike effector nuclease has been reported. In the current study, the mechanisms relating to Cyp17a1 that are involved in the development of sexual traits, especially gonadal differentiation and testicular development, were characterized. We found that the cyp17a1-deficient fish at 3 months postfertilization (mpf) were all fertile males with normal testis and spermatogenesis but compromised male-typical mating behaviors and secondary sex characters (SSCs), including breeding tubercles, body pigmentation, and anal fin coloration. These results demonstrate that spermatogenesis and testicular development are not as susceptible to androgen deficiency compared with the formation of male-typical SSCs and mating behaviors in zebrafish. The differentiation of the juvenile ovary into the mature ovary failed during the critical sexual differentiation stage. This all-male phenotype of the cyp17a1-deficient fish could be restored with testosterone or estradiol treatment. For testicular development in cyp17a1deficient fish, a gradually increasing number of spermatozoa and testis hypertrophy from 3 to 6 mpf were observed, accompanied by constitutively upregulated pituitary gonadotropin FSH subunit b (fshb). The hypertrophic testis and enhanced spermatogenesis in the cyp17a1-deficient fish at 6 mpf could be effectively rescued by fshb depletion. These results confirm that adequate estrogen is essential for maintaining ovarian differentiation, and they provide new insight into the role of FSHb in male testicular development and spermatogenesis. (Endocrinology 159: 3549-3562, 2018) M ating success and fecundity result from proper coordination of the development and expression of various sexual traits, including reproductive organs, mating behaviors, and secondary sex characters (SSCs). It is well established that sex steroid hormones exert considerable influence on the formation of these sexual traits in both mammals and fish (1-8). Recently, zebrafish have emerged as a well-developed model for the reproductive research of the steroidogenic pathway (see below), as zebrafish possess several advantages, including the ease of fertility evaluation and gonadal dissection, observability of germ cells in vivo, and, in particular, the successfully adopted knockout strategy (7, 9-13). In the current study, sexual traits were deeply characterized from the cytochrome P450 (cyp) 17A1 (cyp17a1)-deficient zebrafish, a model that has defective synthesis of androgens (6).