Targeting NR1D1 in organ injury: challenges and prospects.

Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.

Lacidipine attenuates TNF-α-induced cardiomyocyte apoptosis.

This study was designed to investigate whether lacidipine elicited a protective role on cardiomyocyte against apoptosis induced by TNF-α. Neonatal rat cardiomyocytes were randomly assigned into different groups. TUNEL staining was utilized to detect apoptosis, and caspase-3 and caspse-12 were determined. To explore the underlying mechanism, Z-ATAD-FMK (a selective caspase-12 inhibitor) was used to identify the key molecule involved. TNF-α increased caspase-3 expression, which was mediated by increased caspase-12 expression. In the meantime, apoptosis was significantly induced by TNF-α. Lacidipine lowered caspase-12 and caspase-3 expression, and cardiomyocyte apoptosis induced by TNF-α. The results suggest that lacidipine attenuates TNF-α -induced apoptosis via inhibition of caspase-12 and caspase-3 successively.

Κ-opioid receptor stimulation improves endothelial function in hypoxic pulmonary hypertension.

The present study was designed to investigate the effect of κ-opioid receptor stimulation with U50,488H on endothelial function and underlying mechanism in rats with hypoxic pulmonary hypertension (HPH). Chronic hypoxia-induced HPH was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. Relaxation of pulmonary artery in response to acetylcholine (ACh) was determined. Expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO production, total antioxidant capacity (T-AOC), gp91(phox) expression and nitrotyrosine content were measured. The effect of U50,488H administration during chronic hypoxia was investigated. Administration of U50,488H significantly decreased mPAP and right ventricular hypertrophy as evidenced by reduction in RVP and RVHI. These effects were mediated by κ-opioid receptor. In the meantime, treatment with U50,488H significantly improved endothelial function as evidenced by enhanced relaxation in response to ACh. Moreover, U50,488H resulted in a significant increase in eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary artery of HPH rats. In addition, the activity of eNOS was enhanced, but the activity of iNOS was attenuated in the pulmonary artery of chronic hypoxic rats treated with U50,488H. On the other hand, U50,488H markedly blunted HPH-induced elevation of gp91(phox) expression and nitrotyrosine content in pulmonary artery, and these effects were blocked by nor-BNI, a selective κ-opioid receptor antagonist. These data suggest that κ-opioid receptor stimulation with U50,488H improves endothelial function in rats with HPH. The mechanism of action might be attributed to the preservation of eNOS activity, enhancement of eNOS phosphorylation, downregulation of iNOS activity and its antioxidative/nitrative effect.

Vasculoprotective effect of U50,488H in rats exposed to chronic hypoxia: role of Akt-stimulated NO production.

Impairment of pulmonary endothelium function in the pulmonary artery is a direct result of chronic hypoxia. This study is to investigate the vasculoprotective effects of U50,488H (a selective κ-opioid receptor agonist) and its underlying mechanism in hypoxia-induced pulmonary artery endothelial functional injury. Chronic hypoxia was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. The pulmonary vascular dysfunction, effect of nitric oxide synthase inhibitor (l-NAME) on the relaxation of U50,488H, and level of nitric oxide (NO) were determined. In vitro, the signaling pathway involved in the anti-apoptotic effect of U50,488H was investigated. Cultured endothelial cells were subjected to simulated hypoxia, and cell apoptosis was determined by TUNEL staining. U50,488H (1.25 mg/kg) significantly reduced RVP and RVHI in hypoxia. U50,488H markedly improved both pulmonary endothelial function (maximal vasorelaxation in response to ACh: 74.9 ± 1.8%, n = 6, P <0.01 vs. hypoxia for 2 wk group) and increased total NO production (1.65 fold). U50,488H relaxed the pulmonary artery rings of the hypoxic rats. This effect was partly abolished by l-NAME. In cells, U50,488H both increased NO production and reduced hypoxia-induced apoptosis. Moreover, pretreatment with nor-binaltorphimine (nor-BNI, a selective κ-opioid receptor antagonist), PI3K inhibitor, Akt inhibitor or l-NAME almost abolished anti-apoptotic effect exerted by U50,488H. U50,488H resulted in increases in Akt and eNOS phosphorylation. These results demonstrate that pretreatment with U50,488H attenuates hypoxia-induced pulmonary vascular endothelial dysfunction in an Akt-dependent and NO-mediated fashion.

Combined interventional and surgical treatment for acute aortic type a dissection.

Surgical repair and endovascular stent-graft placement are both therapies for thoracic aortic dissection. A combination of these two approaches may be effective in patients with type A dissection. In this study, we evaluated the prognosis of this combined technique. From December 2003 to December 2006, 15 patients with type A dissection were admitted to our institute; clinical data were retrospectively reviewed. Follow-up was performed at discharge and approximately 12 months after operation. Endovascular stent-graft placement by interventional radiology and surgical repair for reconstruction of aortic arch was performed in all patients. Total arch replacement for distal arch aneurysm was carried out under deep hypothermia with circulatory arrest; antegrade-selected cerebral perfusion was used for brain protection. Four patients concomitantly received a coronary artery bypass graft. Hospital mortality rate was 6.7%; the patient died of cerebral infarction. Neurological complications developed in two patients. Multi-detector-row computed tomography scans performed before discharge revealed complete thrombosis of the false lumen in six patients and partial thrombosis in eight patients. At the follow-up examination, complete thrombosis was found in another three patients, aortic rupture, endoleaks, or migration of the stent-graft was not observed and injuries of peripheral organs or anastomotic endoleaks did not occur. For patients with aortic type A dissection, combining intervention and surgical procedures is feasible, and complete or at least partial thrombosis of the false lumen in the descending aorta can be achieved. This combined approach simplified the surgical procedures and shortened the circulatory arrest time, minimizing the necessity for further aortic operation.

Combined interventional and surgical treatment for acute aortic type a dissection.

BACKGROUND: Surgical repair and endovascular stent-graft placement are both therapies for thoracic aortic dissection. A combination of these two approaches may be effective in patients with type A dissection. In this study, we evaluated the prognosis of this combined technique. METHODS: From December 2003 to December 2006, 15 patients with type A dissection were admitted to our institute; clinical data were retrospectively reviewed. Follow-up was performed at discharge and approximately 12 months after operation. RESULTS: Endovascular stent-graft placement by interventional radiology and surgical repair for reconstruction of aortic arch was performed in all patients. Total arch replacement for distal arch aneurysm was carried out under deep hypothermia with circulatory arrest; antegrade-selected cerebral perfusion was used for brain protection. Four patients concomitantly received a coronary artery bypass graft. Hospital mortality rate was 6.7%; the patient died of cerebral infarction. Neural complications developed in two patients. Multi-detector-row computed tomography scans performed before discharge revealed complete thrombosis of the false lumen in six patients and partial thrombosis in eight patients. At the follow-up examination, complete thrombosis was found in another three patients, aortic rupture, endoleaks or migration of the stent-graft was not observed and injuries of peripheral organs or anastomotic endoleaks did not occur. CONCLUSIONS: For patients with aortic type A dissection, combining intervention and surgical procedures is feasible, and complete or at least partial thrombosis of the false lumen in the descending aorta can be achieved. This combined approach simplified the surgical procedures and shortened the circulatory arrest time, minimizing the necessity for further aortic operation.