Active-site cysteine 215 sulfonation targets protein tyrosine phosphatase PTP1B for Cullin1 E3 ligase-mediated degradation.

Reactive oxygen species (ROS), released as byproducts of mitochondrial metabolism or as products of NADPH oxidases and other processes, can directly oxidize the active-site cysteine (Cys) residue of protein tyrosine phosphatases (PTPs) in a mammalian cell. Robust degradation of irreversibly oxidized PTPs is essential for preventing accumulation of these permanently inactive enzymes. However, the mechanism underlying the degradation of these proteins was unknown. In this study, we found that the active-site Cys215 of endogenous PTP1B is sulfonated in H9c2 cardiomyocytes under physiological conditions. The sulfonation of Cys215 led PTP1B to exhibit a conformational change, and drive the subsequent ubiquitination and degradation of this protein. We then discovered that Cullin1, an E3 ligase, interacts with the Cys215-sulfonated PTP1B. The functional impairment of Cullin1 prevented PTP1B from oxidation-dependent ubiquitination and degradation in H9c2 cells. Moreover, delivery of the terminally oxidized PTP1B resulted in proteotoxicity-caused injury in the affected cells. In conclusion, we elucidate how sulfonation of the active-site Cys215 can direct turnover of endogenous PTP1B through the engagement of ubiquitin-proteasome system. These data highlight a novel mechanism that maintains PTP homeostasis in cardiomyocytes with constitutive ROS production.

Calmodulin: The switch button of calcium signaling.

Calmodulin (CaM), a calcium sensor, decodes the critical calcium-dependent signals and converts them into the driving force to control various important cellular functions, such as ion transport. This small protein has a short central linker to connect two globular lobes and each unit is composed of a pair of homologous domains (HD) which are responsible for calcium binding. The conformation of each HD is sensitive to the levels of the intracellular Ca2+ concentrations while the flexible structure of the central domain enables its interactions with hundreds of cellular proteins. Apart from calcium binding, posttranslational modifications (PTMs) also contribute to the modulations of CaM functions by affecting its protein-protein interaction networks and hence drawing out the various downstream signaling cascades. In this mini-review, we first aim to elucidate the structural features of CaM and then overview the recent studies on the engagements of calcium binding and PTMs in Ca2+/CaM-mediated conformational alterations and signaling events. The mechanistic understanding of CaM working models is expected to be a key to decipher the precise role of CaM in cardiac physiology and disease pathology.

Eating right for a healthier heart: Food choice contributes to cardiometabolic benefits and reduction of carotid intima-media thickness.

OBJECTIVES: Diets may alter an individual's metabolism and inflammation, collectively leading to the modulation of cardiovascular health and disease process. The aim of this study was to investigate the effects of diets and diet-associated metabolites on metabolic profiles, inflammatory status, and severity of atherosclerosis. METHODS: A cross-sectional study was conducted with 81 healthy adults in Taiwan. A food frequency questionnaire was obtained for evaluating dietary intake. Carotid intima-media thickness (CIMT), a relevant marker of subclinical atherosclerosis, was measured by ultrasound. RESULTS: Consumption of instant noodles and sugary beverages was associated with worse metabolic profiles. In contrast, the intake of fresh fruit and green vegetables was correlated with better metabolic parameters. Sugary beverages were dose-dependently correlated with higher expressions of toll-like receptor (TLR)2 and TLR4 on monocytes, whereas fresh fruit intake was associated with lower TLRs. Furthermore, consumption of green vegetables, brown rice, and >2000 mL/d of water was inversely correlated with CIMT. The diet-associated metabolites including trimethylamine N-oxide and S-adenosyl-l-homocysteine, were positively associated with CIMT, whereas l-lysine and l-carnitine were associated with decreased CIMT. Interestingly, intake of strict vegetarian foods resulted in lower serum total cholesterol levels without a detectable effect on inflammatory status or CIMT. CONCLUSIONS: Independent of the pattern of strict vegetarian foods, individuals who consumed more vegetables, fresh fruit, and water showed better cardiovascular health as evidenced by their metabolic and inflammatory status and CIMT results.

Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction.

AIMS: The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes. METHODS AND RESULTS: Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function. CONCLUSIONS: PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.

Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury.

Acute myocardial ischemia/reperfusion (I/R) injury is a significant, unsolved clinical puzzle. In the disease context of acute myocardial infarction, reperfusion remains the only effective strategy to salvage ischemic myocardium, but it also causes additional damage. Myocardial I/R injury is composed of four types of damage, and these events attenuate the benefits of reperfusion therapy. Thus, inventing new strategies to conquer I/R injury is an unmet clinical need. A variety of pathological processes and mediators, including changes in the pH, generation of reactive oxygen radicals, and intracellular calcium overload, are proposed to be crucial in I/R-related cell injury. Among the intracellular events that occur during I/R, we stress the importance of protein phosphorylation signaling and elaborate its regulation. A variety of protein kinase pathways could be activated in I/R, including reperfusion injury salvage kinase and survivor-activating factor enhancement pathways, which are critical to cardiomyocyte survival. In addition to serine/threonine phosphorylation signaling, protein tyrosine phosphorylation is also critical in multiple cell functions and survival. However, the roles of protein kinases and phosphatases in I/R have not been extensively studied yet. By better understanding the mechanisms of I/R injury, we may have a better chance to develop new strategies for I/R injury and apply them in the clinical patient care.

High serum adipocyte fatty acid binding protein level as a potential biomarker of aortic arterial stiffness in hypertensive patients with metabolic syndrome.

BACKGROUND: The adipocyte-fatty-acid-binding protein (A-FABP) has been implicated in arterial stiffness, metabolic syndrome (MetS), and cardiovascular disease. We aimed to determine the relationship among serum A-FABP concentration, cardiometabolic risk factors, and central arterial stiffness in a hypertensive population. METHODS: Fasting blood samples and baseline characteristics were obtained from 110 hypertensive patients. Serum A-FABP concentrations were determined by enzyme immunoassay kit. High arterial stiffness was defined as carotid-femoral pulse wave velocity values >10m/s via the SphygmoCor system. RESULTS: Patients with MetS and high arterial stiffness accounted for 67.3% and 42.7% of the study population, respectively. Serum A-FABP was positively associated with MetS and high arterial stiffness (P=0.006 and P<0.001, respectively). Multivariable stepwise linear regression analysis of the significant variables of arterial stiffness revealed that logarithmically transformed A-FABP (log-A-FABP, ß=0.278, P=0.002) was positively correlated arterial stiffness in hypertensive patients. Subgroup analysis revealed that log-A-FABP (ß=0.327, P=0.003), age (ß=0229, P=0.032), and triglyceride (ß=0.307, P=0.004) were significantly positively correlated with arterial stiffness in hypertensive patients with MetS. CONCLUSIONS: Elevated A-FABP concentration could be a predictor for MetS and arterial stiffness in hypertensive patients.

Serum resistin as an independent marker of aortic stiffness in patients with coronary artery disease.

BACKGROUND: Subjects with higher carotid-femoral pulse wave velocity (cfPWV) will be at an increased risk for cardiovascular (CV) events in future. Resistin is an inflammatory mediator and a biomarker of CV diseases. We evaluated the association between serum resistin and aortic stiffness in patients with coronary artery disease (CAD). METHODS: A total of 104 patients with CAD were enrolled in this study. cfPWV was measured using the SphygmoCor system. Patients with cfPWV >10 m/s were defined as the high aortic stiffness group. RESULTS: Thirty-seven patients (35.6%) had high aortic stiffness and higher percentages of diabetes (p = 0.001), were of older age (p = 0.001) and had higher waist circumference (p < 0.001), systolic blood pressure (p = 0.027), pulse pressure (p = 0.013), high-sensitivity C-reactive protein (p < 0.001) and resistin levels (p < 0.001) but lower estimated glomerular filtration rate (p = 0.009) compared to subjects with low aortic stiffness. After adjusting for factors significantly associated with aortic stiffness by multivariate logistic regression analysis, serum resistin (odds ratio = 1.275, 95% confidence interval: 1.065-1.527, p = 0.008) was also found to be an independent predictor of aortic stiffness in patients with CAD. CONCLUSIONS: Serum resistin level is a biomarker for aortic stiffness in patients with CAD.

Low serum adiponectin level is associated with metabolic syndrome and is an independent marker of peripheral arterial stiffness in hypertensive patients.

BACKGROUND: Adiponectin has been implicated in metabolic syndrome (MetS) and arterial stiffness (AS). We aim to determine the relationship between serum adiponectin concentration as well as peripheral AS in hypertensive patients. METHODS: Fasting blood samples were obtained from 101 hypertensive patients. Brachial-ankle pulse wave velocity (baPWV) was measured with an automatic pulse wave analyzer. Serum adiponectin concentrations were determined by using an enzyme immunoassay kit. A baPWV >14.0 m/s was defined as high AS. RESULTS: MetS and high AS were present in 62.4 and 71.3% of the study population. Adiponectin was inversely associated with MetS and high AS (both P < 0.001). Serum higher high-density lipoprotein cholesterol (HDL-C) (P = 0.012), triglycerides (P = 0.001), C-reactive protein (P < 0.001), insulin (P = 0.027), body weight (P = 0.002), waist circumference (WC, P < 0.001), body mass index (P = 0.001) bilateral-baPWV (P < 0.001), systolic blood pressure (SBP, P < 0.001), diastolic blood pressure (DBP, P = 0.012), pulse pressure (P = 0.019), homeostasis model assessment of insulin resistance (HOMA1-IR (P = 0.026) and HOMA2-IR (P = 0.020)) and lower glomerular filtration rate (GFR, P = 0.029) were significantly associated with high AS. Multivariate logistic regression analysis of the factors significantly associated with AS revealed that adiponectin [odds ratio: 0.932, 95% confidence interval (CI) 0.881-0.985, P = 0.012], and SBP (odds ratio: 1.059, 95% CI 1.008-1.113, P = 0.022) were the independent predictors of arterial stiffness in hypertensive patients. Subgroup analysis revealed that SBP (odds ratio: 1.126, 95% CI 1.024-1.237, P = 0.014) and GFR (odds ratio: 0.858, 95% CI 0.739-0.996, P = 0.043) were the independent predictors of arterial stiffness in hypertensive patients without MetS; adiponectin (odds ratio: 0.909, 95% CI 0.931-0.996, P = 0.040) was the independent predictor of arterial stiffness in hypertensive patients with MetS. CONCLUSIONS: Hypoadiponectinemia has positive association with MetS and peripheral AS in hypertensive patients.

High serum resistin levels are associated with peripheral artery disease in the hypertensive patients.

BACKGROUND: Hypertension is a risk factor for peripheral arterial disease (PAD). Subjects with PAD are at increased risk of future cardiovascular (CV) events. Resistin is involved in the pathological processes of CV diseases. The aim of this study is to investigate whether resistin level is correlated with PAD in hypertensive patients. METHODS: One hundred and twenty-four hypertensive patients were enrolled in this study. Ankle-brachial index (ABI) values were measured using the automated oscillometric method. An ABI value < 0.9 defined the low ABI group. Anthropometric analysis with waist circumference and body mass index, and fasting serum levels of blood urea nitrogen, creatinine, glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total calcium, phosphorus, and high-sensitivity C-reactive protein (hs-CRP) were measured using standard enzymatic automated methods. Serum levels of human resistin were determined using a commercially available enzyme immunoassay. RESULTS: Eighteen hypertensive patients (14.5%) were included in the low ABI group. Hypertensive patients in the low ABI group were older (p = 0.043) and had higher serum creatinine (p < 0.001), high-sensitivity C-reactive protein (hs-CRP; p = 0.013), and resistin (p < 0.001) levels but a lower estimated glomerular filtration rate (p = 0.002) than patients in the normal ABI group. After the adjustment for factors that were significantly associated with PAD on multivariate logistic regression analysis, serum resistin (odds ratio [OR], 1.176; 95% confidence interval [CI], 1.028-1.345; p = 0.018) was also an independent predictor of PAD in hypertensive patients. CONCLUSIONS: A high serum resistin level is an independent predictor of PAD in hypertensive patients.

Association of serum leptin levels with central arterial stiffness in coronary artery disease patients.

BACKGROUND: Serum adipokines have roles in the development of arterial stiffness. Our aim was to investigate the relationship of leptin and the surrogate marker carotid-femoral pulse wave velocity (cfPWV) in coronary artery disease (CAD) patients. METHODS: Fasting blood samples were obtained from 105 CAD patients. cfPWV was measured with the SphygmoCor system. A cfPWV > 10 m/s was defined as high arterial stiffness, and ≤ 10 m/s as low arterial stiffness. RESULTS: Thirty-seven patients (35.2 %) had high arterial stiffness, and had a higher percentage of diabetes (P = 0.001), hypertension (P = 0.010), older age (P = 0.001), and higher systolic blood pressure (SBP) (P < 0.001), diastolic blood pressure (DBP) (P = 0.021), pulse pressure (P = 0.014), and serum leptin level (P = 0.002) compared to patients with low arterial stiffness. Serum leptin levels correlated with the number of angiographically documented stenotic coronary artery vessels (P < 0.001). After adjusting for factors significantly associated with arterial stiffness, multivariate logistic regression analysis showed that leptin (odds ratio = 1.026, 95 % confidence interval: 1.002-1.051, P = 0.037) was a significant independent predictor of arterial stiffness. CONCLUSIONS: Increasing serum concentration of leptin correlated positively with the total number of stenotic coronary arteries, and serum leptin level may predict the development of arterial stiffness in CAD patients.

Serum osteoprotegerin is associated with arterial stiffness assessed according to the cardio-ankle vascular index in hypertensive patients.

AIM: Arterial stiffness is recognized to be an independent risk factor for cardiovascular morbidity and mortality. Recent studies have found that osteoprotegerin (OPG) is associated with increased pulse wave velocity and may reflect endothelial dysfunction. The aim of this study was to evaluate the relationship between the serum OPG level and arterial stiffness in hypertensive patients using the cardio-ankle vascular index (CAVI). METHODS: Fasting blood samples were obtained from 115 hypertensive patients and 52 healthy participants. The CAVI value was derived using the waveform device (CAVI-VaSera VS-1000). The serum OPG levels were measured using a commercially available enzyme-linked immunosorbent assay. A CAVI value of ≥9 defined the high arterial stiffness group. RESULTS: Sixty-five hypertensive patients (56.5%) were included in the high arterial stiffness group. Diabetes (p=0.032), smoking (p=0.044), age (p < 0.001), systolic blood pressure (p=0.001), diastolic blood pressure (p=0.024), pulse pressure (p=0.046) and the creatinine (p=0.013) and serum OPG (p < 0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group, while the glomerular filtration rate (p=0.003) was lower in the high arterial stiffness group than in the low arterial stiffness group among the hypertensive patients. The results of the Spearman's rank correlation coefficient test also indicated a strong positive correlation between the OPG and CAVI values (r=0.484, p < 0.001) in the hypertensive patients. In addition, a multivariate logistic regression analysis showed that age (odds ratio: 1.162, 95% confidence interval (CI): 1.070-1.263, p < 0.001), diastolic blood pressure (odds ratio: 1.109, 95% CI: 1.033-1.190, p=0.004), and serum OPG level (odds ratio: 1.275, 95% CI: 1.030-1.580, p=0.026) were independent predictors of arterial stiffness in hypertensive patients. CONCLUSIONS: The serum OPG level is positively associated with arterial stiffness in hypertensive patients.

Serum osteopontin level correlates with carotid-femoral pulse wave velocity in geriatric persons.

Osteopontin (OPN) is involved in the regulation of vascular calcification processes. The aim of this study was to evaluate the relationship between fasting serum OPN concentration and carotid-femoral pulse wave velocity (cfPWV) in geriatric persons. Fasting blood samples were obtained from 93 geriatric persons. cfPWV were performed by SphygmoCor system. Serum OPN levels were measured using a commercially available enzyme-linked immunosorbent assay. Geriatric adults who had diabetes (P = 0.007) or dyslipidemia (P = 0.029) had higher cfPWV levels than those without diabetes or dyslipidemia. The univariable linear regression analysis showed that age (P = 0.002), waist circumference (P = 0.048), body mass index (P = 0.004), systolic blood pressure (P = 0.001), diastolic blood pressure (P = 0.036), pulse pressure (P = 0.017), creatinine (P = 0.002), and log-OPN level (P = 0.001) were positively correlated with cfPWV levels, while the high-density lipoprotein cholesterol (HDL-cholesterol) level (P = 0.007) and glomerular filtration rate (P = 0.001) were negatively correlated with cfPWV levels among the geriatric adults. Multivariable forward stepwise linear regression analysis of the significant variables also showed that log-OPN (ß = 0.233, R (2) = 0.123, regression coefficient: 1.868, P = 0.011) was still an independent predictor of cfPWV levels in geriatric persons.

Association of serum osteoprotegerin levels with carotid-femoral pulse wave velocity in hypertensive patients.

Osteoprotegerin (OPG) has been implicated in the process of vascular stiffness. The aim of this study was to evaluate the relationship between fasting serum OPG concentration and carotid-femoral pulse wave velocity (c-f PWV) in hypertensive patients. Fasting blood samples were obtained from 184 participants with or without hypertension. c-f PWV were performed by SphygmoCor system. Serum OPG levels were measured using a commercially available enzyme-linked immunosorbent assay. Hypertensive patients who had diabetes had higher c-f PWV levels than those without diabetes (P=.031). The univariable linear regression analysis showed that age (P<.001), systolic blood pressure (P=.003), pulse pressure (r=0.287; P=.003), log-BUN (P=.011), Cre (P<.001), and log-OPG concentration (P<.001) were positively correlated with c-f PWV levels, while the glomerular filtration rate (P=.005) and HDL-C level (P=.024) was negatively correlated with c-f PWV levels among the hypertensive patients. Multivariable forward stepwise linear regression analysis of the significant variables also showed that log-OPG (ß=0.312, regression coefficient: 1.736; 95% confidence interval, 0.809-2.663; P<.001) was still an independent predictor of c-f PWV levels in hypertensive patients. Serum OPG levels positively associated with c-f PWV levels in hypertensive patients.

[Not Available].

UNLABELLED: Saphenous vein graft (SVG) failure secondary to degeneration can cause significant problems after coronary artery bypass surgery (CABG). Repeat revascularization by percutaneous coronary intervention can be performed after SVG failure but is often associated with less favourable clinical outcome. Treatment for chronic total occlusion (CTO) of native vessels after SVG failure among patients with prior CABG is frequently performed. However, revascularization of CTO vessels in patients with prior CABG may be more complex and require more frequent use of the retrograde approach. Good septal or epicardial collateral channels are usually needed for the retrograde CTO approach. However, suitable native collateral channels may be absent and alternative retrograde routes should be considered. In this case report, we described a patient who had prior CABG and developed recurrent angina after SVG failure. His native CTO lesion was successfully revascularized by using a totally occluded vein graft as a retrograde conduit. KEY WORDS: Chronic total occlusions; Coronary artery bypass grafts; Percutaneous coronary intervention; Saphenous vein graft.