Associations between myeloperoxidase and paraoxonase-1 and type 2 diabetes in patients with ischemic heart disease.

BACKGROUND: The phrase "dysfunctional high-density lipoprotein" has been developed in the literature to describe the particle which loses its basic role- anti-oxidative and anti-inflammatory activity. In this porcess, the significance of enzymes- pro-oxidant myeloperoxidase (MPO) and antioxidant paraoxonase-1 (PON-1) from the perspective of HDL-C function has been noted. AIMS: The objective of this study was to analyze the associations between two enzymes -MPO and PON-1 and type 2 diabetes (T2DM) in patients with ischemic heart disease (IHD). METHODS: An observational cross-sectional study including 70 patients with IHD of whom 35 had also T2DM, and 35 had no T2DM. Laboratory tests (MPO, PON-1, fasting glucose, glycated hemoglobin, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and high-sensitivity C-reactive protein) were performed. RESULTS: The study revealed a significant difference in the serum concentration of the enzymes between patients with IHD with and without T2DM. Our results showed increased MPO concentration levels in diabetic patients. The analysis also revealed that T2DM is independently associated with an increase in MPO levels. Simultaneously, a decrease in PON-1 levels was observed in patients with T2DM. The study also revealed that T2DM is independently associated with a decrease in PON-1 levels. CONCLUSIONS: In patients with type 2 diabetes the profile of enzymes involved in high-density lipoprotein metabolism in patients with IHD is worse than in patients without T2DM. The increase in the levels of MPO, an enzyme with oxidative and atherogenic properties and on a decrease in PON-1 levels, an enzyme with antioxidant and atheroprotective properties is observed.

Forensic significance of intracardiac heme oxygenase-1 expression in acute myocardial ischemia.

Heme oxygenase-1 (HO-1), an inducible stress-response protein, exerts anti-oxidant and anti-apoptotic effects. However, its significance in forensic diagnosis of acute ischemic heart diseases (AIHD) such as myocardial infarction (MI) is still unknown. We examined the immunohistochemical expression of HO-1 in the heart samples to discuss their forensic significance to determine acute cardiac ischemia. The heart samples were obtained from 23 AIHD cases and 33 non-AIHD cases as controls. HO-1 positive signals in cardiomyocyte nuclear were detected in 78.2% of AIHD cases, however, that were detected in only 24.2% control cases with statistical difference between AIHD and non-AIHD groups. In contrast to HO-1 protein expression, there was no significant difference in the appearance of myoglobin pallor regions and leukocyte infiltration in the hearts between AIHD and non-AIHD groups. From the viewpoints of forensic pathology, intracardiac HO-1 expression would be considered a valuable marker to diagnose AIHD as the cause of death.

Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.

Yorkshire swine were fed standard diet (n = 7) or standard diet containing applesauce rich in caffeic acid with Lactobacillus plantarum (n = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The L. plantarum-applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum-applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum-applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function.NEW & NOTEWORTHY Colonization of the gut microbiome with certain strains of L. Plantarum has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with L. Plantarum-applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.

PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) and pyroptosis both play important roles in myocardial infarction. This study was designed to test the hypothesis that PCSK9 regulates pyroptosis in cardiomyocytes during chronic myocardial ischemia. Primary cardiomyocytes were isolated from WT and PCSK9-/- mice. HL-1 cardiomyocytes were used to set up PCSK9-deficient (PCSK9-/-) and PCSK9-upregulated (PCSK9CRISPRa) cardiomyocyte cell line with CRISPR/Cas9 knockout or activation plasmid. Additional studies were performed with chronic myocardial ischemia in WT and PCSK9-/- mice. We observed that PCSK9 initiates mitochondrial DNA (mtDNA) damage, activates NLRP3 inflammasome signaling (NLRP3, ASC, Caspase-1, IL-1ß, and IL-18), and subsequently induces Caspase-1-dependent pyroptosis. There was an intense expression of PCSK9 and pyroptosis marker, GSDMD-NT, in the zone bordering the infarct area. PCSK9-/- significantly suppressed expression of NLRP3 inflammasome signaling, GSDMD-NT, and LDH release. Furthermore, serum levels of PCSK9, NLPR3 inflammasome signaling, and pyroptosis (GSDMD and LDH release) were significantly elevated in patients with chronic myocardial ischemia as compared to those in age-matched healthy subjects. Human hearts with recent infarcts also showed high expression of PCSK9 and GSDMD-NT in the border zone similar to that in the infarcted mouse heart. These observations provide compelling evidence for the role of PCSK9 in regulating Caspase-1-dependent pyroptosis via mtDNA damage and may qualify pro-inflammatory cytokines and pyroptosis as potential targets to treat PCSK9-related cardiovascular diseases.

Glycogen synthase kinase-3ß inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction.

Inflammasome-promoted sterile inflammation following cardiac damage is critically implicated in heart dysfunction after myocardial infarction (MI). Glycogen synthase kinase-3 (GSK-3ß) is a prominent mediator of the inflammatory response, and high GSK-3 activity is associated with various heart diseases. We investigated the regulatory mechanisms of GSK-3ß in activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model with successful induction of MI on days 2-28. An in vitro investigation was performed using newborn rat/human cardiomyocytes and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. GSK-3ß inhibition markedly improved myocardial dysfunction and prevented remodeling, with parallel reduction in the parameters of NLRP3 inflammasome activation after MI. GSK-3ß inhibition reduced NLRP3 inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes. GSK-3ß's interaction with activating signal cointegrator (ASC) as well as GSK-3ß inhibition reduced ASC phosphorylation and oligomerization at the tissues and cellular levels. Taken together, these data show that GSK-3ß directly mediates NLRP3 inflammasome activation, causing cardiac dysfunction in MI.

Hexokinase II dissociation alone cannot account for changes in heart mitochondrial function, morphology and sensitivity to permeability transition pore opening following ischemia.

We previously demonstrated that hexokinase II (HK2) dissociation from mitochondria during cardiac ischemia correlates with cytochrome c (cyt-c) loss, oxidative stress and subsequent reperfusion injury. However, whether HK2 release is the primary signal mediating this ischemia-induced mitochondrial dysfunction was not established. To investigate this, we studied the effects of dissociating HK2 from isolated heart mitochondria. Mitochondria isolated from Langendorff-perfused rat hearts before and after 30 min global ischemia ± ischemic preconditioning (IPC) were subject to in vitro dissociation of HK2 by incubation with glucose-6-phosphate at pH 6.3. Prior HK2 dissociation from pre- or end-ischemic heart mitochondria had no effect on their cyt-c release, respiration (± ADP) or mitochondrial permeability transition pore (mPTP) opening. Inner mitochondrial membrane morphology was assessed indirectly by monitoring changes in light scattering (LS) and confirmed by transmission electron microscopy. Although no major ultrastructure differences were detected between pre- and end-ischemia mitochondria, the amplitude of changes in LS was reduced in the latter. This was prevented by IPC but not mimicked in vitro by HK2 dissociation. We also observed more Drp1, a mitochondrial fission protein, in end-ischemia mitochondria. IPC failed to prevent this increase but did decrease mitochondrial-associated dynamin 2. In vitro HK2 dissociation alone cannot replicate ischemia-induced effects on mitochondrial function implying that in vivo dissociation of HK2 modulates end-ischemia mitochondrial function indirectly perhaps involving interaction with mitochondrial fission proteins. The resulting changes in mitochondrial morphology and cristae structure would destabilize outer / inner membrane interactions, increase cyt-c release and enhance mPTP sensitivity to [Ca2+].

Exploring Impaired SERCA Pump-Caused Alternation Occurrence in Ischemia.

Impaired sarcoplasmic reticulum (SR) calcium transport ATPase (SERCA) gives rise to Ca2+ alternans and changes of the Ca2+release amount. These changes in Ca2+ release amount can reveal the mechanism underlying how the interaction between Ca2+ release and Ca2+ uptake induces Ca2+ alternans. This study of alternans by calculating the values of Ca2+ release properties with impaired SERCA has not been explored before. Here, we induced Ca2+ alternans by using an impaired SERCA pump under ischemic conditions. The results showed that the recruitment and refractoriness of the Ca2+ release increased as Ca2+ alternans occurred. This indicates triggering Ca waves. As the propagation of Ca waves is linked to the occurrence of Ca2+ alternans, the "threshold" for Ca waves reflects the key factor in Ca2+ alternans development, and it is still controversial nowadays. We proposed the ratio between the diastolic network SR (NSR) Ca content (Cansr) and the cytoplasmic Ca content (Ca i ) (Cansr/Ca i ) as the "threshold" of Ca waves and Ca2+ alternans. Diastolic Cansr, Ca i , and their ratio were recorded at the onset of Ca2+ alternans. Compared with certain Cansr and Ca i , the "threshold" of the ratio can better explain the comprehensive effects of the Ca2+ release and the Ca2+ uptake on Ca2+ alternans onset. In addition, these ratios are related with the function of SERCA pumps, which vary with different ischemic conditions. Thus, values of these ratios could be used to differentiate Ca2+ alternans from different ischemic cases. This agrees with some experimental results. Therefore, the certain value of diastolic Cansr/Ca i can be the better "threshold" for Ca waves and Ca2+ alternans.

[Study of energy metabolism enzymes and state of cardiovascular system in elderly and senile age patients.]

The present work introduces data on studying the activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) and the state of the cardiovascular system in elderly and senile people who applied to polyclinic "Health zone" in Baku. 60 people on an enzimopatiya and 87 people on a condition of cardiovascular system were examined. The examined persons were found the decreased myocardial blood flow, ischemic heart disease (IHD), against increased PK and LDH. Statistically significant differences in the activity of enzymes depending on gender, age were established, and changes in the bioelectric activity of the heart during an ECG were detected.

PRMT4 overexpression aggravates cardiac remodeling following myocardial infarction by promoting cardiomyocyte apoptosis.

Myocardial infarction due to coronary artery occlusion leads to adverse cardiac remodeling and heart failure. Apoptotic loss of cardiomyocytes near the ischemia area enlarges infarct area and promotes cardiac remodeling. Protein arginine methyltransferase 4 (PRMT4), a type I protein arginine methyltransferase, is involved in many cellular processes. Here we aimed to investigate the role of PRMT4 in cardiomyocyte apoptosis and myocardial infarction. We found that PRMT4 expression was markedly increased in ischemic heart and hypoxic cardiomyocytes. In vivo, cardiac-specific overexpression of PRMT4 in mice resulted in decreased survival rate, reduced left ventricular function, and aggravated cardiac remodeling following myocardial infarction. Mechanistically, PRMT4 overexpression promoted hypoxia-induced cardiomyocytes apoptosis, while its inhibition abolished these effects. Taken together, our work suggested an essential role of PRMT4 in myocardial infarction and cardiomyocyte apoptosis.

Effects of the combination of tanshinone IIA and puerarin on cardiac function and inflammatory response in myocardial ischemia mice.

BACKGROUND: Ventricular remodeling is a major pathological process of normal heart failure. With the aging of society, poor diet control, social, psychological and other risk factors in our country, the incidence of myocardial infarction and hypertension is reported to increase yearly. Many treatment methods have effectively delayed the occurrence of ventricular remodeling. However, in order to prevent and delay the occurrence and development of ventricular remodeling, the new treatment strategy cannot be ignored. METHODS: In this study, we used male C57BL/6 mice (8 weeks old), weight 23 g-27 g, SPF grade. According to the established methods of the research group, the left anterior descending branch of the coronary artery (LAD) was used to make the model of myocardial ischemia, and which was evaluated by the change of EF value in mice. The experiment included seven groups: sham operation group, model group, metoprolol group, puerarin group, tanshinone IIA group, tanshinone IIA: puerarin =1:1 group, tanshinone IIA: puerarin =1:2 group. The changes of cardiac function in each group were observed by echocardiography and hemodynamics after the drug delivery cycle was 3d, 7d, 14d and 28d. Detection of 3d serum enzyme indexes LDH, CK and CK-MB by automatic biochemical analyzer. The expression of CD11b, F4/80, Ly6C in cardiac tissues were detected by flow cytometry at 3d and 7d. The expression of IL-1ß and TNF- α in serum were detected by ELISA. IL-1ß, IL-6, IL-10, iNOS and other related genes were detected by RT-PCR method. HE, Masson staining and immunohistochemical staining were used to observe the changes of myocardial histomorphology in mice. We also examined the effects of different drug treatments on the proliferation and function of Raw264.7 cells, H9C2 cells and HUVECs. Western blot examined the effects of different drug treatments on the expression of inflammatory pathway related proteins TLR4 and C/EBP-ß. RESULTS: 1. Echocardiographic results showed that with the prolongation of ischemic time, the ejection fraction of the model group, the shortening rate of the short axis of the left ventricle, the flow rate of the outflow tract were significantly decreased, and the structure of the ventricle was significantly changed. Hemodynamic tests showed that the maximum and maximum rate of decline in the post-ischemia model group were significantly reduced, with increased systolic and diastolic volume, and a decrease in pressure difference. After treatment with drugs, all groups improved, but tanshinone IIA: puerarin = 1:1 group can significantly improve the above indicators after 28d of administration, which can effectively relieve the deterioration of cardiac function caused by acute myocardial infarction. 2. After administration for 3 and 7 days, the inflammatory cell CD11b monocytes and the F4/80 phenotype macrophages in heart tissue were detected by flow cytometry, and it was found that tanshinone IIA: puerarin = 1:1 can inhibit the release of inflammatory cells. The results of RT-PCR showed that the tanshinone IIA: puerarin = 1:1 group significantly improved the expression of inflammatory cytokines such as IL-1ß, IL-6, IL-10, and iNOS. In the immunohistochemical analysis of iNOS and Arg-1, the tanshinone IIA and puerarin 1:1 treatment group was able to inhibit the expression of M1 macrophages in the early stage of inflammation and promote the expression of M2 macrophages. 3. The cardiac index increased significantly and the serum TGF-ß increased after 28d. The combination of tanshinone IIA and puerarin could significantly reduce these indexes. HE, Masson, Sirius red and immunohistochemical staining were found in the combination of tanshinone IIA and puerarin can significantly reduce the structure of acute ischemic myocardial cell damage and interstitial edema, reduce collagen synthesis, and fibroblasts release, thereby inhibiting myocardial fibrosis and heart remodeling. 4. MTT assay showed a significantly greater proliferation of above two cells types treated with tanshinone IIA: puerarin =1:1 and more nodes and meshes were found in tanshinone IIA: puerarin =1:1 group compared with other groups. 5. The combination of tanshinone IIA and puerarin could regulate inflammation through inhibiting the expression of TLR4 protein, but up-regulating the expression of C/EBP-ß protein. CONCLUSION: The combination of tanshinone IIA and puerarin inhibits the immersion of inflammatory cells. Improving hemodynamics by improving cardiac function, reducing the destruction of cardiac myocytes, reducing collagen synthesis, inhibiting myocardial fibrosis and ventricular remodeling. Through the whole experiment, tanshinone IIA: puerarin = 1:1 is the best.

Investigating the effects and possible mechanisms of danshen- honghua herb pair on acute myocardial ischemia induced by isoproterenol in rats.

Danshen (salvia miltiorrhiza) and honghua(Carthamus tinctorius) were traditional herb pair with promoting blood circulation and removing blood stasis actions, in China. Both were widely used to treat cardiovascular diseases (CVD) for hundreds years, especially shown definite advantage in the treatment of ischemic heart disease (IHD). However, the mechanism of danshen-honghua herb pair (DHHP) in the treatment of IHD was still unclear. This study was focused on examining the effects and possible mechanisms of DHHP in rats with acute myocardial ischemia induced by isoproterenol (ISO). The results suggested that DHHP significantly ameliorated the myocardial tissue abnormalities, notablely inhibited the elevation of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), creatinekinase isoenzyme (CK-MB) and cardiac troponin T (CTn-T) in plasma, obviously decreased the plasma levels of Tumor Necrosis Factor α (TNF-α), outstandingly inhibited the reduction of superoxide dismutase (SOD), catalase (CAT) caused by ISO, significantly inhibited the high expression of Bcl-2 assaciated X protein (Bax) and nuclear transcriptionfactor-κBP65 (NF-κBP65) protein, significantly induced the low expression of B-cell lymphoma-2 (Bcl-2) protein in acute myocardial ischemia rats. DHHP can obviously ameliorate hemodynamic parameters. In summary, DHHP can significantly improve myocardial ischemia in acute myocardial ischemia model rats caused by ISO. Anti-free radicals, anti-peroxidation, inhibition of cell apoptosis and anti- inflammation maybe are the potential mechanisms of DHHP anti-myocardial ischemia in acute myocardial ischemia rats in duced by ISO.

Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study.

Tryptophan is an essential amino acid. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan-kynurenine pathway, is positively associated with cardiac events, and may be relevant to cancer. We used Mendelian Randomization to obtain unconfounded estimates of the association of IDO1 with ischemic heart disease (IHD), ischemic stroke and their risk factors, all-cancer, cancer of the prostate, lung and bronchus, and breast. We obtained genetic instruments independently and strongly (p-value < 5 × 10-8) predicting plasma IDO1 from a proteome genome-wide association study (GWAS), and applied them to consortia GWAS of the outcomes, including the UK Biobank SOFT CAD GWAS (cases < = 76 014, non-cases < = 264 785) for IHD. Estimates were obtained using inverse variance weighting; with MR-Egger, weighted median and MR-PRESSO as sensitivity analyses. IDO1 was inversely associated with IHD (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (CI) 0.93 to 1.00, p-value = 0.04), diabetes (OR 0.91, 95% CI 0.85 to 0.97) and prostate cancer (OR 0.96, 95% CI 0.93 to 0.99) with a directionally consistent estimate for stroke (OR 0.98, 95% CI 0.95 to 1.02) but not with blood pressure, or the other cancers considered. IDO1 might be a potential therapeutic target for IHD, diabetes and prostate cancer.

GSK3ß inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage.

AIMS: Myocardial infarction induces myocardial injury and tissue damage. During myocardial infarction strong cellular response is initiated to salvage the damaged tissues. This response is associated with the induction of different signaling pathways. Of these, the canonical Wnt signaling is increasingly important for its prosurvival cellular role, making it a good candidate for the search of new molecular targets to develop therapies to prevent heart failure in infarcted patients. METHODS: Herein we report that GSK3ß regulates the canonical Wnt signaling in C57Bl6 mice hearts. GSK3ß is a canonical Wnt pathway inhibitor. Using GSK3ß inhibitors and inducing myocardial injury (MI) in Lrp5-/- mice model we show that GSK3ß phosphorylation levels regulate downstream canonical Wnt pathway genes in the ischemic heart. In the setting of MI, myocardial damage assessment usually correlates with functional and clinical outcomes. Therefore, we measured myocardial injury size in Wt and Lrp5-/- mice in the presence and absence of two different GSK3 inhibitors prior to MI. Myocardial injury was independent of GSK3 inhibitor treatments and GSK3ß expression levels. RESULTS: These studies support a central role for GSK3ß in the activation of the canonical Wnt pathway in the Wt heart. Although LRP5 is protective against myocardial injury, GSK3ß expression levels do not regulate heart damage.

P66shc and its role in ischemic cardiovascular diseases.

Oxidative stress caused by an imbalance in the formation and removal of reactive oxygen species (ROS) plays an important role in the development of several cardiovascular diseases. ROS originate from various cellular origins; however, the highest amount of ROS is produced by mitochondria. One of the proteins contributing to mitochondrial ROS formation is the adaptor protein p66shc, which upon cellular stresses translocates from the cytosol to the mitochondria. In the present review, we focus on the role of p66shc in longevity, in the development of cardiovascular diseases including diabetes, atherosclerosis and its risk factors, myocardial ischemia/reperfusion injury and the protection from it by ischemic preconditioning. Also, the contribution of p66shc towards cerebral pathologies and the potential of the protein as a therapeutic target for the treatment of the aforementioned diseases are discussed.

Ginsenoside Rg1 inhibits myocardial ischaemia and reperfusion injury via HIF-1 α-ERK signalling pathways in a diabetic rat model.

The aim of this study was to observe the effects of HIF-1α activation on myocardial I/R in diabetes. Diabetes was induced in an experimental rat model, and regulators of HIF-1α including KC7F2, deferoxamine and ginsenoside Rg1 were administered to observe the changes on diabetic rats. The results demonstrated that HIF-1α activation could effectively reduce myocardial injury following I/R in diabetic hearts via ERK but not MMP-2 signalling pathways. This activation promoted myocardial apoptosis, which was accompanied by modulation of Bax/Bcl-2, caspase-3 and caspase-9 expression following deferoxamine administration. Ginsenoside Rg1 application but not Re can activate HIF-1α, resulting in a similar protectively effect on these pathology processes. Our data demonstrated that ginsenoside Rg1 has a potential therapeutic effect by protecting diabetic hearts after myocardial injury following I/R via HIF-1α activation.

Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure.

BACKGROUND: After myocardial infarction (MI), delayed progression or reversal of cardiac remodeling is a prime target to limit advanced chronic heart failure (HF). However, the temporal kinetics of lipidomic and systemic metabolic signaling is unclear in HF. There is no consensus on metabolic and lipidomic signatures that influence structure, function, and survival in HF. Here we use genetic knock out model to delineate lipidomic, and metabolic changes to describe the role of lipoxygenase in advancing ischemic HF driven by leukocyte activation with signs of non-resolving inflammation. Bioactive lipids and metabolites are implicated in acute and chronic HF, and the goal of this study was to define the role of lipoxygenase in temporal kinetics of lipidomic and metabolic reprogramming in HF. MATERIALS AND METHODS: To address this question, we used a permanent coronary ligation mouse model which showed profound metabolic and lipidomic reprogramming in acute HF. Additionally, we defined the lipoxygenase-mediated changes in cardiac pathophysiology in acute and chronic HF. For this, we quantitated systemic metabolic changes and lipidomic profiling in infarcted heart tissue with obvious structural remodeling and cardiac dysfunction progressing from acute to chronic HF in the survival cohort. RESULTS: After MI, lipoxygenase-derived specialized pro-resolving mediators were quantitated and showed lipoxygenase-deficient mice (12/15LOX-/-) biosynthesize epoxyeicosatrienoic acid (EETs; cypoxins) to facilitate cardiac healing. Lipoxygenase-deficient mice reduced diabetes risk biomarker 2-aminoadipic acid with profound alterations of plasma metabolic signaling of hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids in acute HF, thereby improved survival. CONCLUSION: Specific lipoxygenase deletion alters lipidomic and metabolic signatures, with modified leukocyte profiling that delayed HF progression and improved survival. Future studies are warranted to define the molecular network of lipidome and metabolome in acute and chronic HF patients.

Things get broken: the hypoxia-inducible factor prolyl hydroxylases in ischemic heart disease.

A major challenge in developing new treatments for myocardial infarction (MI) is an improved understanding of the pathophysiology of hypoxic tissue damage and the activation of endogenous adaptive programs to hypoxia. Due to the relevance of oxygen in metabolism, molecular adaptation to hypoxia driven by the hypoxia-inducible factors (HIFs) and the HIF-regulating prolyl hydroxylase domain enzymes (PHDs) is pivotal for the survival of cells and tissue under hypoxia. The heart under ischemic stress will extensively rely on these mechanisms of endogenous cardiac protection until hypoxia becomes too severe. In the past, work from several laboratories has provided evidence that inhibition of HIF-regulating PHDs might improve the outcome in ischemic heart disease (IHD) potentially because the adaptive mechanisms are boosted early and vigorously. Here, we review the role of the HIF hydroxylase pathway in IHD and highlight the potential of PHD inhibitors as a new treatment for MI with special regard to acute ischemia, reperfusion, and regeneration of the heart.

Intestinal Alkaline Phosphatase Deficiency Is Associated with Ischemic Heart Disease.

BACKGROUND: We have previously shown that the deficiency of the gut enzyme intestinal alkaline phosphatase (IAP) is associated with type 2 diabetes mellitus (T2DM) in humans, and mice deficient in IAP develop the metabolic syndrome, a precipitant of T2DM and ischemic heart disease (IHD). We hypothesized that IAP deficiency might also be associated with IHD in humans. We aimed to determine the correlation between the IAP level and IHD in humans. METHODS AND RESULTS: The IHD patients were recruited from the National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh, and the control healthy participants were recruited from a suburban community of Dhaka. We determined the IAP level in the stools of 292 IHD patients (187 males, 105 females) and 331 healthy control people (84 males, 247 females). We found that compared to controls, IHD patients have approx. 30% less IAP (mean ± SEM: 63.7 ± 3.5 vs. 44.9 ± 2.1 U/g stool, respectively; p < 0.000001), which indicates that IAP deficiency is associated with IHD, and a high level of IAP is probably protective against IHD in humans. The adjusted generalized linear model (GLM) of regression analysis predicted a strong association of IAP with IHD (p = 0.0035). Multiple logistic regression analysis showed an independent inverse relationship between the IAP level and the IHD status (odds ratio, OR = 0.993 with 95% CI 0.987-0.998; p < 0.01). CONCLUSIONS: IAP deficiency is associated with IHD, and a high level of IAP might be protective against IHD.

Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation.

BACKGROUND/AIMS: Coronary angiogenesis is an important protective mechanism in response to myocardial ischemia in coronary artery disease. However, the underlying mechanisms remain largely unclear. Here, we investigated the role of CaMKII activation in ischemia-induced cardiac angiogenesis. METHODS: Repetitive transient ischemia model was established in C57/BL6 mice by daily multiple episodes (3 times/day) of short time (5 min) occlusion of the left anterior descending coronary artery for 7 days. Coronary angiogenesis was detected by immunofluorescent staining. RT-qPCR and Western blot analyses were used to detect the mRNA and protein levels of CaMKII, p-CaMKII and VEGF. Primary cardiac microvascular endothelial cells (CMECs) were isolated to investigate the effects of KN93 on cell proliferation and migration in hypoxic condition. RESULTS: We found that angiogenesis was induced in the ischemic myocardium and suppressed by chronic intraperitoneal injection of CaMKII inhibitor KN93. RT-qPCR and Western blot analyses showed that myocardial ischemia induced an increased expression and autophosphorylation of CaMKII. VEGF expression was increased in the ischemia model but blunted by KN93. Moreover, KN93 suppressed the proliferation and migration of cardiac endothelial cells in hypoxic condition in which the protein expression of CaMKII, p-CaMKII and VEGF was increased. CONCLUSION: CaMKII is an important mediator for the ischemia-induced coronary angiogenesis, in which CaMKII-triggered VEGF expression plays a key role.

Mst1: Function and Mechanism in Brain and Myocardial Ischemia Reperfusion Injury.

Mammalian STE20-like kinase-1 (Mst1) is a generally expressed apoptosis-promoting kinase and a key bridgebuilder of apoptotic signaling in the etiology of tissue injury. Despite the fact that the biological function of Mst1 and its role in the cell's signalling network have yet to be determined, however, there is a lot of evidence that Mst1 plays an important role in cell death which results from tissue injury. Previous studies have shown that Mst1 is not only a target for some apoptosis- related molecules such as caspase 3 and P53, but also act as an activator of these proteinases to magnify apoptosis signal pathways. This article reviews the role of Mst1 in the signaling pathways which is related with the neuronal cell apoptosis or microglia activation following myocardial and brain injury. Therefore, this work contributes to better understanding of the pathological process of myocardial and brain injury.