Mortality rate after coronary revascularization in heart failure patients with coronary artery disease.

AIMS: Coronary artery disease (CAD) is a common cause of heart failure (HF). It remains unclear who, when and why to direct towards coronary revascularization. The outcomes of coronary revascularization in HF patients are still a matter of debate nowadays. This study aims to evaluate the effect of revascularization strategy on all-cause of death in the context of ischaemic HF. METHODS AND RESULTS: An observational cohort was conducted on 692 consecutive patients who underwent coronary angiography at the University Hospital of Toulouse between January 2018 and December 2021 for either a recent diagnosis of HF or a decompensated chronic HF, and in whom coronary angiograms showed at least 50% obstructive coronary lesion. The study population was divided into two groups according to the performance or not of a coronary revascularization procedure. The living status (alive or dead) of each of the study's participants was observed by April 2022. Seventy-three per cent of the study population underwent coronary revascularization either by percutaneous coronary intervention (66.6%) or coronary artery bypass grafting (6.2%). Baseline characteristics including age, sex and cardiovascular risk factors did not differ between the invasive and conservative groups, respectively. Death occurred in 162 study participants resulting in an all-cause mortality rate of 23.5%; 26.7% of observed deaths have occurred in the conservative group versus 22.2% in the invasive group (P = 0.208). No difference in survival outcomes has been observed over a mean follow-up period of 2.5 years (P = 0.140) even after stratification by HF categories (P = 0.132) or revascularization modalities (P = 0.366). CONCLUSIONS: Findings from the present study showed comparable all-cause mortality rates between groups. Coronary revascularization does not modify short-term survival outcomes in HF patients compared with optimal medical therapy alone outside the setting of acute coronary syndrome.

Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis.

The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species-dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A- and reactive oxygen species-dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A-dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C(2)-ceramide or H(2)O(2). In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H(2)O(2)-induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed significant upregulation of ceramide and inhibition of SphK1. It is noteworthy that SphK1 inhibition, ceramide accumulation, and concomitantly infarct size and cardiomyocyte apoptosis were significantly decreased in MAO-A-deficient animals. In conclusion, we show for the first time that the upregulation of ceramide/sphingosine 1-phosphate ratio is a critical event in MAO-A-mediated cardiac cell apoptosis. In addition, we provide the first evidence linking generation of reactive oxygen species with SphK1 inhibition. Finally, we propose sphingolipid metabolites as key mediators of postischemic/reperfusion cardiac injury.

IL-26 in the induced sputum is associated with the level of systemic inflammation, lung functions and body weight in COPD patients.

Background: Chronic inflammatory process is the main link in COPD pathogenesis, which causes structural changes in the respiratory tract and lungs. In overweight patients, an adipose tissue could contribute to activation of the inflammatory process. Therefore, it is highly important to identify potential biomarkers of inflammation for patients with COPD and obesity. The aim of this study was to investigate the role of interleukin-26 (IL-26) and evaluate the relationship between the level of systemic inflammation, lung function, and body mass index (BMI) in patients with COPD. Patients and methods: Eighty-three patients with COPD in the stable condition (stage 2 according to the 2016 Global Initiative for Chronic Obstructive Lung Disease recommendations), aged 40-70 years, were included in the study. All patients were divided into 2 groups: obese (n=53) (BMI - 30.0-39.9 kg/m2) and non-obese (n=30) (BMI - 18.5-24.9 kg/m2). We conducted patients' examination, spirometry, induced the sputum, determined the level of C-reactive protein (CRP), leptin in serum and IL-26 in sputum. Results: Obese and non-obese COPD patients had a significant increase in IL-26 compared with healthy subjects by 2.3 and 2.6 (P=0.0003). We also observed a higher level of CRP by 1.38 times (P=0.0008), compared with the rate in non-obese COPD patients, and by 1.8 times (P=0.015) higher concentration level of leptin compared with healthy subjects. The sputum IL-26 level had positive correlation with BMI, CRP, and leptin, and a negative - with forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity. Leptin level had positive correlation with BMI and CRP, and negative with FEV1, FEV1/forced vital capacity. Conclusion: Obese COPD patients had a higher level of persistent systemic inflammation than non-obese ones, which is confirmed by a significant increase of CRP and leptin in serum. The data confirm that IL-26 can be considered as a perspective marker to detect the inflammation level in lung tissue of COPD patients.

Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury.

BACKGROUND: Serotonin (5-hydroxytryptamine [5-HT]), released by activated platelets during cardiac ischemia, is metabolized by the mitochondrial enzyme monoamine oxidase A (MAO-A). Because hydrogen peroxide is one of the byproducts of 5-HT degradation by MAO-A, we investigated the potential role of reactive oxygen species generated by MAOs in 5-HT-dependent cardiomyocyte death and post-ischemia-reperfusion cardiac damage. METHODS AND RESULTS: Treatment of isolated adult rat cardiomyocytes with 5-HT induced intracellular oxidative stress and cell apoptosis. The apoptotic cascade triggered by 5-HT involves release of cytochrome c, upregulation of proapoptotic Bax protein, and downregulation of antiapoptotic Bcl-2 protein. These effects were prevented by inhibition of amine transporter or MAO, antioxidants, or iron chelation. In contrast, cardiomyocyte apoptosis was only slightly affected by the 5-HT(2B) receptor antagonist SB 206553. In vivo, inhibition of MAO-A largely reduced myocardial ultrastructural damage induced by 30 minutes of ischemia followed by 60 minutes of reperfusion in the rat heart. Cardioprotective effects of MAO inhibitors were associated with the prevention of postischemic oxidative stress, neutrophil accumulation, and mitochondrial-dependent cell death and were not reverted by SB 206553. Administration of MAO-A inhibitors during ischemia was still effective in preventing cardiac damage. CONCLUSIONS: Our results supply the first direct evidence that oxidative stress induced by MAO is responsible for receptor-independent apoptotic effects of 5-HT in cardiomyocytes and postischemic myocardial injury. These findings provide new insight into the mechanisms of 5-HT action in the heart and may constitute the basis for novel therapies.

Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion.

Reactive oxygen species (ROS) contribute to the ischemia-reperfusion injury. In kidney, the intracellular sources of ROS during ischemia-reperfusion are still unclear. In the present study, we investigated the role of the catecholamine-degrading enzyme monoamine oxidases (MAOs) in hydrogen peroxide (H2O2) generation after reperfusion and their involvement in cell events leading to tissue injury and recovery. In a rat model of renal ischemia-reperfusion, we show concomitant MAO-dependent H2O2 production and lipid peroxidation in the early reperfusion period. Rat pretreatment with the irreversible MAO inhibitor pargyline resulted in the following: i) prevented H2O2 production and lipid peroxidation; ii) decreased tubular cell apoptosis and necrosis, measured by TUNEL staining and histomorphological criteria; and iii) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression. MAO inhibition also prevented Jun N-terminal kinase phosphorylation and promoted extracellular signal-regulated kinase activation, two mitogen-activated protein kinases described as a part of a "death" and "survival" pathway after ischemia-reperfusion. This work demonstrates the crucial role of MAOs in mediating the production of injurious ROS, which contribute to acute apoptotic and necrotic cell death induced by renal ischemia-reperfusion in vivo. Targeted inhibition of these oxidases could provide a new avenue for therapy to prevent renal damage and promote renal recovery after ischemia-reperfusion.

Prevention of apoptotic and necrotic cell death, caspase-3 activation, and renal dysfunction by melatonin after ischemia/reperfusion.

The pineal hormone melatonin has been reported to protect tissue from oxidative damage. This study was designed to determine whether melatonin could prevent cell events leading to tissue injury and renal dysfunction after ischemia/reperfusion (I/R). Using an in vivo rat model of I/R, we show a significant increase in kidney malondialdehyde concentrations, reflecting lipid peroxidation, and cell apoptosis measured by TUNEL staining. This apoptotic cell death was associated with an increase in the activity of the proapoptotic factor caspase-3, determined by fluorometric protease activity assay. Histomorphological analysis of ischemic kidneys revealed that the most extensive tubular necrosis occurred at 24 and 48 h after reperfusion, which correlated with peak elevations in blood urea nitrogen and creatinine. Rat pretreatment with melatonin prevented lipid peroxidation, cell apoptosis, and necrosis and blocked caspase-3 activity. The prevention of tissue injury was associated with the improvement of renal function as shown by the decrease in blood urea nitrogen and creatinine concentrations. The demonstration that melatonin prevents postreperfusion apoptotic and necrotic cell death and improves renal function suggests that melatonin may represent a novel therapeutic approach for prevention of I/R injury.

Apelin, a promising target for type 2 diabetes treatment?

Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM.

Involvement of peripheral benzodiazepine receptor in the oxidative stress, death-signaling pathways, and renal injury induced by ischemia-reperfusion.

The peripheral benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell death. In the present study we investigated the role of PBR in the regulation of signaling pathways leading to apoptotic and necrotic damage and renal dysfunction in a rat model of ischemia-reperfusion. Renal ischemia-reperfusion led to extended tubular apoptosis and necrosis that were associated with peroxidative damage, high levels of proapoptotic Bax expression, and low levels of antiapoptotic Bcl-2 expression, cleavage of death substrate, poly(ADP-ribose) polymerase (PARP), and activation of a key effector of apoptosis, caspase-3. Rat pretreatment with a novel PBR antagonist, SSR180575, significantly decreased postreperfusion oxidative stress and tubular apoptosis and necrosis. This effect was associated with inhibition of caspase-3 activation and PARP cleavage, upregulation of Bcl-2, and downregulation of Bax. Furthermore, inhibition of PBR accelerated the recovery of normal renal function, as assessed by measurement of levels of plasma creatinine and blood urea nitrogen. These findings reveal a role for PBR as a modulator of necrotic and apoptotic cell death induced by ischemia-reperfusion and suggest that regulation of PBR may provide new therapeutic implications for the prevention of acute renal failure.