Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme in the metabolism of aldehydes and may have beneficial cardiovascular effects for conditions such as cardiac hypertrophy, heart failure, myocardial I/R injury, reperfusion, arrhythmia, coronary heart disease and atherosclerosis. In this study we investigated the role of ALDH2 in the progression of atherosclerosis and the underlying mechanisms, with a focus on endoplasmic reticulum (ER) stress. A clinical study was performed in 248 patients with coronary heart disease. The patients were divided into two groups according to their ALDH2 genotype. Baseline clinical characteristics and coronary angiography were recorded, and the coronary artery Gensini score was calculated. Serum levels of 4-hydroxy-2-nonenal (4-HNE) were detected. The clinical study revealed that the mutant ALDH2 genotype was an independent risk factor for coronary heart disease. ALDH2 gene polymorphism is closely associated with atherosclerosis and the severity of coronary artery stenosis. Serum levels of 4-HNE were significantly higher in patients with the mutant ALDH2 genotype than in patients with the wild-type ALDH2 genotype. As an in vitro model of atherosclerosis, rat smooth muscle cells (SMCs) were treated with oxygenized low-density lipoprotein (ox-LDL), which significantly elevated the levels of ER markers glucose-regulated protein78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated eukaryotic translation initiation factor α subunit (p-eIF2α), activating transcription factor-4 (ATF-4), CEBP homologous protein (CHOP) and 4-HNE in the cells. All the ox-LDL-induced responses were significantly attenuated in the presence of Alda-1 (an ALDH2 activating agent), and accentuated in the presence of daidzin (an ALDH2 inhibitor). Furthermore, pretreatment with ALDH2 activator Alda-1 significantly decreased ox-LDL-induced apoptosis. Similarly, overexpression of ALDH2 protected SMCs against ox-LDL-induced ER stress as well as ER stress-induced apoptosis. These findings suggest that ALDH2 may slow the progression of atherosclerosis via the attenuation of ER stress and apoptosis in smooth muscle cells.
Arsenic trioxide (ATO; As O ) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC of ∼30-50 μM at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 μM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2•- levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2•- levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2•- level and GSH depletion.
Objective: To investigate the clinical features and the diagnostic and follow-up value of acute fulminant myocarditis (AFM) in children.Methods: A total of 20 children diagnosed with AFM admitted to our department were reviewed, and the clinical manifestations; pathogenic examination results; myocardial injury biomarkers; and electrocardiography, echocardiogram, and cardiovascular magnetic resonance (CMR) results were analyzed.Results: Twenty children with AFM, including 12 males and 8 females, aged 3–16 years, were analyzed. The initial symptoms were abdominal pain, vomiting, fatigue, syncope, and convulsions. All children had significantly increased hs-cTnT and NT-pro BNP. In addition to nonspecific ST-T changes, there were 10 cases of complete atrioventricular block, 2 cases of advanced atrioventricular block, and 1 case of ventricular tachycardia. Echocardiography showed an increase in the cardiac chamber sizes in 15 patients and a decrease in left ventricular ejection fraction (LVEF) in 17 patients. There were 16 patients with abnormal CMR findings, including 13 cases of high T2-weighted image (T2WI) signal and 14 cases of late gadolinium enhancement (LGE). In the patients who underwent CMR within 14 days of onset, the sensitivity of T2WI and LGE and the positive diagnosis rate were higher than in those who underwent CMR after 14 days, but the difference was not statistically significant. CMR was followed up in 10 patients: 7 patients returned to normal, 2 patients still had mild LGE, and 1 patient developed inflammatory dilated cardiomyopathy. All patients were treated with high-dose immunoglobulin, 11 of whom received high-dose immunoglobulin combined with glucocorticoids. Eight patients received temporary pacemakers, and 1 patient received ECMO. None of the patients died. The peak of hs-cTnT was significantly higher in the glucocorticoid group than in the unused glucocorticoid group (2853.4 ± 2217.2 and 1124.7 ± 527.3 pg/ml, respectively).Conclusion: Children with AFM have unique clinical features. Early identification and effective treatment can reduce the mortality rate and improve the prognosis. CMR is highly sensitive in the diagnosis of ARM, especially within 14 days of onset, and is a useful noninvasive imaging technique for the early identification of AFM in children. The dynamic observation and follow-up of children with AFM through CMR can guide clinical decision-making and prognosis assessment.
Cardiac electrophysiological disorders, in particular arrhythmias, are a key cause of morbidity and mortality throughout the world. There are two basic requirements for arrhythmogenesis: an underlying substrate and a trigger. Altered conduction velocity (CV) provides a key substrate for arrhythmogenesis, with slowed CV increasing the probability of re-entrant arrhythmias by reducing the length scale over which re-entry can occur. In this review, we examine methods to measure cardiac CV in vivo and ex vivo, discuss underlying determinants of CV, and address how pathological variations alter CV, potentially increasing arrhythmogenic risk. Finally, we will highlight future directions both for methodologies to measure CV and for possible treatments to restore normal CV.
Loss of endothelial function (LEF) post-PCI may contribute to both acute and long-term complications. A protective effect of BNP on endothelium was suggested previously. Flow-mediated vasodilation (FMD) of the brachial artery, as well as plasma levels of endothelin, BNP, Pro BNP and corin were measured before and following routine PCI. 49 patients with normal baseline endothelial function were recruited. 30 patients developed LEF and were randomized to i.v. nesiritide (the commercially available recombinant form of human BNP) or saline infusion for 3 h. Patients who developed LEF post-PCI had reduced baseline plasma corin levels and their BNP/ProBNP ratio was reduced after the procedure. Nesiritide infusion significantly improved FMD both immediately (Nesiritide versus saline: 2.87+/-0.78% versus 0.51+/-0.25%, P=0.007) and 24 h after the treatment (2.52+/-0.69% versus 0.72+/-0.32%, P=0.025). The elevated plasma ET-1 was reduced by Nesiritide (0.38+/-0.11 fmol/ml 24 h post-PCI versus 0.16+/-0.02 fmol/ml 24 h post BNP, P=0.047), but remained unchanged in saline group (0.39+/-0.21 fmol/ml versus 0.42+/-0.23 fmol/ml, P=0.749). Systemic LEF post-PCI is a frequent event. It may be related to impaired cleavage of ProBNP to BNP. Short-term i.v. nesiritide improves systemic LEF post-PCI.
This study was conducted to evaluate the cardioprotective property of the aqueous extract of lavender flower (LFAE). The myocardial ischemia/reperfusion (I/R) injury of rat was prepared by Langendorff retrograde perfusion technology. The heart was preperfused with K-H solution containing LFAE for 10 min before 20 minutes global ischemia, and then the reperfusion with K-H solution was conducted for 45 min. The left ventricular developed pressure (LVDP) and the maximum up/downrate of left ventricular pressure (±dp/dtmax) were recorded by physiological recorder as the myocardial function and the myocardial infarct size was detected by TTC staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the effluent were measured to determine the myocardial injury degree. The superoxide anion dismutase (SOD) and malondialdehyde (MDA) in myocardial tissue were detected to determine the oxidative stress degree. The results showed that the pretreatment with LFAE significantly decreased the myocardial infarct size and also decreased the LDH, CK activities, and MDA level, while it increased the LVDP, ±dp/dtmax, SOD activities, and the coronary artery flow. Our findings indicated that LFAE could provide protection for heart against the I/R injury which may be related to the improvement of myocardial oxidative stress states.
Calpain, calcineurin (CaN), and nuclear factor of activated T cell (NFAT) play a key role in the development of atrial fibrillation. Patients with valvular heart disease (VHD) are prone to develop atrial fibrillation (AF). Thus, our current study was aimed at investigating whether activation of calpain-CaN-NFAT pathway is associated with the incidence of AF in the patients with VHD and diabetes. The expressions of calpain 2 and alpha- and beta-isoforms of CaN catalytic subunit (CnA) as well as NFAT-c3 and NFAT-c4 were quantified by quantitative reverse transcription-polymerase chain reaction in atrial tissues from 77 hospitalized patients with VHD and diabetes. The relevant protein content was measured by Western blot and calpain 2 in human atrium was localized by immunohistochemistry. We found that the expressions of calpain 2, CnA alpha and CnA beta, and NFAT-c3 but not NFAT-c4 were significantly elevated in the samples from patients with AF compared to those with sinus rhythm (SR). Elevated protein levels of calpain 2 and CnA were observed in patients with AF, and so was the enhanced localization of calpain 2. We thereby concluded that CaN together with its upstream molecule, calpain 2, and its downstream effector, NFAT-c3, might contribute to the development of AF in patients with VHD and diabetes.
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