RESUMO
The reduced density of cardiac autonomic nerves plays an important role in malignant arrhythmia after myocardial infarction (MI). Previous studies have shown that there is an interaction between the brain and the heart, and fastigial nucleus electrostimulation (FNS) promotes central nerve regeneration. Whether and how it can promote cardiac nerve regeneration after MI and the underlying mechanisms remain unknown. This study investigated whether FNS promotes cardiac nerve regeneration and reduces malignant arrhythmia inducibility in a post-infarction rat model. Ninety-eight Wistar rats were randomly assigned to Sham control, MI (left anterior descending coronary artery ligation without FNS), FNS (MI plus FNS), and FNL (fastigial nucleus lesion plus FNS plus MI) groups. The frequency of malignant arrhythmia was significantly lower in the FNS group than in the MI and FNL groups. The density of cardiac autonomic nerves was less in the MI group than in the Sham group, which was promoted by FNS. The nerve growth factor (NGF) mRNA expression was downregulated in the MI group compared to the Sham group, which was significantly enhanced by FNS. The expression levels of norepinephrine (NE) and acetylcholine (ACh) were higher and lower respectively in the MI and FNL groups than in the Sham group. After FNS, NE concentration was reduced and Ach level was elevated compared to the MI group. These data suggested that FNS promoted the regeneration of cardiac autonomic nerves and reduced the incidence of malignant arrhythmias in MI rat model. The mechanisms might involve up-regulation of NGF mRNA expression, decrease of NE release and increase of ACh release.
Assuntos
Terapia por Estimulação Elétrica , Infarto do Miocárdio , Animais , Arritmias Cardíacas , Núcleos Cerebelares , Modelos Animais de Doenças , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Regeneração Nervosa , Neurotransmissores , Ratos , Ratos WistarRESUMO
FACT (Facilitates Chromatin Transactions) is a heterodimeric protein complex involved in RNA polymerase II transcription elongation, playing essential roles in chromatin remodeling during transcription, replication, and DNA damage repair. The FACT subunit hSpt16 is essential for nucleosome reorganization. The N-terminal domain of hSpt16 (hSpt16-NTD) was recently described as a histone (H3-H4)2-binding domain; however, its mode of interaction remains unknown. In this study, we solved the structure of hSpt16-NTD437 at 2.19â¯Å and found that a long-disordered region (hSpt16-LDR), after the main body of hSpt16-NTD, is a novel histone-binding motif. Furthermore, hSpt16-LDR interaction with (H3-H4)2 is H3 N-terminal tail-independent. Therefore, Spt16-NTD is a histone H3-H4-specific binding domain with a distinct mechanism of interaction between histones and histone chaperones.
Assuntos
Proteínas de Ciclo Celular/química , Histonas/metabolismo , Fatores de Transcrição/química , Animais , Proteínas de Ciclo Celular/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Fatores de Transcrição/metabolismo , Xenopus laevisRESUMO
Increasing amounts of evidence implicate oxidative stress as having a pivotal role in age-related cerebrovascular dysfunction, which is an important risk factor for the development of cerebrovascular disease. Previous studies have shown that the activation of the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in vascular endothelial cells results in an improvement of vascular function. Pioglitazone, a well-known PPAR-γ agonist, protects against oxidative stress in the rostral ventrolateral medulla by the upregulation of mitochondrial uncoupling protein 2 (UCP2). In this study, we sought to explore the effects and the underlying mechanisms of pioglitazone on age-related oxidative stress elevation and cerebrovascular dysfunction in aging rat cerebral arteries. A natural aging model was constructed and used in these experiments. One-month oral administration of pioglitazone (20 mg·kg·d) ameliorated the production of reactive oxygen species, promoted endothelial nitric oxide synthase phosphorylation and increased the nitric oxide available, thus improving endothelium-dependent relaxation in aging rat cerebral arteries. One-month pioglitazone administration also restored PPAR-γ expression and increased the levels of UCP2 in aging rat cerebral arteries. Using in vitro studies, we demonstrated that pioglitazone attenuated reactive oxygen species levels in aging human umbilical vein endothelial cells through PPAR-γ activation. Furthermore, we found that this occurs in an UCP2-dependent manner. Our study demonstrated that the activation of PPAR-γ by pioglitazone protected against oxidative stress damage in aging cerebral arteries by upregulating UCP2. PPAR-γ may be a new target in treating age-related cerebrovascular dysfunction.
Assuntos
Artérias Cerebrais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Envelhecimento , Animais , Artérias Cerebrais/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Canais Iônicos/genética , Masculino , Proteínas Mitocondriais/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Pioglitazona , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteína Desacopladora 2 , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: Our aim was to evaluate the efficacy and safety of intracoronary autologous bone marrow mesenchymal stem cell (BM-MSC) transplantation in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: In this randomized, single-blind, controlled trial, patients with STEMI (aged 39-76 years) were enrolled at 6 centers in Beijing (The People's Liberation Army Navy General Hospital, Beijing Armed Police General Hospital, Chinese People's Liberation Army General Hospital, Beijing Huaxin Hospital, Beijing Tongren Hospital, Beijing Chaoyang Hospital West Hospital). All patients underwent optimum medical treatment and percutaneous coronary intervention and were randomly assigned in a 1:1 ratio to BM-MSC group or control group. The primary endpoint was the change of myocardial viability at the 6th month's follow-up and left ventricular (LV) function at the 12th month's follow-up. The secondary endpoints were the incidence of cardiovascular event, total mortality, and adverse event during the 12 months' follow-up. The myocardial viability assessed by single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was used to assess LV function. All patients underwent dynamic ECG and laboratory evaluations. This trial is registered with ClinicalTrails.gov, number NCT04421274. RESULTS: Between March 2008 and July 2010, 43 patients who had underwent optimum medical treatment and successful percutaneous coronary intervention were randomly assigned to BM-MSC group (n = 21) or control group (n = 22) and followed-up for 12 months. At the 6th month's follow-up, there was no significant improvement in myocardial activity in the BM-MSC group before and after transplantation. Meanwhile, there was no statistically significant difference between the two groups in the change of myocardial perfusion defect index (p = 0.37) and myocardial metabolic defect index (p = 0.90). The LVEF increased from baseline to 12 months in the BM-MSC group and control group (mean baseline-adjusted BM-MSC treatment differences in LVEF 4.8% (SD 9.0) and mean baseline-adjusted control group treatment differences in LVEF 5.8% (SD 6.04)). However, there was no statistically significant difference between the two groups in the change of the LVEF (p = 0.23). We noticed that during the 12 months' follow-up, except for one death and one coronary microvascular embolism in the BM-MSC group, no other events occurred and alanine transaminase (ALT) and C-reactive protein (CRP) in BM-MSC group were significantly lower than that in the control group. CONCLUSIONS: The present study may have many methodological limitations, and within those limitations, we did not identify that intracoronary transfer of autologous BM-MSCs could largely promote the recovery of LV function and myocardial viability after acute myocardial infarction.