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BackgroundThis study aimed to investigate intracoronary nicorandil treatment on the no-reflow phenomenon (NRP) during primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) and to compare nicorandil with sodium nitroprusside.Material/MethodsPatients with sustained acute STEMI who underwent primary PCI (N=120) were randomly assigned to three groups: the nicorandil-treated group (N=40) had 2 mg of nicorandil injected into the coronary artery at 2 mm beyond the occlusion with balloon pre-dilation; the sodium nitroprusside-treated group (N=40) underwent the same procedure, but with 200 μg of sodium nitroprusside; the control group (N=40) received PCI and balloon pre-dilation only. Coronary angiography, incidence of NRP, hypotensive episodes, ST-segment resolution (STR) rate, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), wall motion score index (WMSI), and left ventricular ejection fraction (LVEF) were measured before and after primary PCI. Major adverse cardiovascular events (MACEs) post-PCI and at three-month follow-up were recorded.ResultsPatients in the sodium nitroprusside and nicorandil groups had significantly improved thrombolysis in myocardial infarction (TIMI) scores, TIMI myocardial perfusion grade (TMPG), and ST-segment elevation resolution (STR) (P<0.05), and a significantly lower incidence of NRP (P=0.013). The incidence of intraoperative hypotension in the sodium nitroprusside group was significantly greater than the nicorandil and control groups (P=0.035).ConclusionsPatients with sustained acute STEMI undergoing primary PCI, treated with intracoronary nicorandil had a reduced incidence of the NRP, improved myocardial perfusion and cardiac function.

Brown adipose tissue is a major thermogenic organ that plays a key role in maintenance of body temperature and whole-body energy homeostasis. Rev-erbα, a ligand-dependent nuclear receptor and transcription repressor of the molecular clock, has been implicated in the regulation of adipogenesis. However, whether Rev-erbα participates in brown fat formation is not known. Here we show that Rev-erbα is a key regulator of brown adipose tissue development by promoting brown adipogenesis. Genetic ablation of Rev-erbα in mice severely impairs embryonic and neonatal brown fat formation accompanied by loss of brown identity. This defect is due to a cell-autonomous function of Rev-erbα in brown adipocyte lineage commitment and terminal differentiation, as demonstrated by genetic loss- and gain-of-function studies in mesenchymal precursors and brown preadipocytes. Moreover, pharmacological activation of Rev-erbα activity promotes, whereas its inhibition suppresses brown adipocyte differentiation. Mechanistic investigations reveal that Rev-erbα represses key components of the TGF-β cascade, an inhibitory pathway of brown fat development. Collectively, our findings delineate a novel role of Rev-erbα in driving brown adipocyte development, and provide experimental evidence that pharmacological interventions of Rev-erbα may offer new avenues for the treatment of obesity and related metabolic disorders.

Rev-erbα is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erbα in myogenic regulation remains largely unknown. Here we show that Rev-erbα exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erbα direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erbα display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erbα activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erbα in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erbα as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erbα activity may have potential utilities to enhance regenerative capacity in muscle diseases.