A chicken and egg conundrum: coronary microvascular dysfunction and heart failure with preserved ejection fraction.
Ohanyan Vahagn; Sisakian Hamayak; Peketi Punita; Parikh Ankur; Chilian William
American journal of physiology. Heart and circulatory physiology
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00154.2018" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00154.2018</a>
AMP-activated kinase "Keaps" ischemia/reperfusion-induced necroptosis under control.
*AMP-Activated Protein Kinases; *AMPK; *Apoptosis; *Ischemia/reperfusion; *Myocardium; *Necroptosis; *Necrosis; Apoptosis; Humans; Myocardial Reperfusion Injury; Myocardium
Kanugula Anantha K; Thodeti Charles K
International journal of cardiology
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijcard.2018.02.053" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2018.02.053</a>
Bile Acid Metabolism in Liver Pathobiology.
Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders.
Chiang John Y L; Ferrell Jessica M
Gene expression
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3727/105221618X15156018385515" target="_blank" rel="noreferrer noopener">10.3727/105221618X15156018385515</a>
Comparing cardioprotetion by DiOHF intervention and ischemic preconditioning.
*Cardioprotecton; *Flavonol; *Ischemia/reperfusion injury; *Ischemic preconditioning; *Ischemic Preconditioning; *Reperfusion Injury; Humans
Chen Yeong-Renn
International journal of cardiology
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijcard.2018.02.019" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2018.02.019</a>
Coronary microvascular Kv1 channels as regulatory sensors of intracellular pyridine nucleotide redox potential.
* NADH; *endothelium; *ion channels; *vascular smooth muscle; *vasodilation; Animals; Coronary Vessels/chemistry; Humans; Microcirculation; Oxidation-Reduction; Potassium Channels; Pyrimidine Nucleotides/*metabolism; Reactive Nitrogen Species/metabolism; Reactive Oxygen Species/metabolism; Voltage-Gated/*physiology
Smooth muscle voltage-gated potassium (Kv) channels are important regulators of microvascular tone and tissue perfusion. Recent studies indicate that Kv1 channels represent a key component of the physiological coupling between coronary blood flow and myocardial oxygen demand. While the mechanisms by which metabolic changes in the heart are transduced to alter coronary Kv1 channel gating and promote vasodilation are unclear, a growing body of evidence underscores a pivotal role of Kv1 channels in sensing the cellular redox status. Here, we discuss current knowledge of mechanisms of Kv channel redox regulation with respect to pyridine nucleotide modulation of Kv1 function via ancillary Kvbeta proteins as well as direct modulation of channel activity via reactive oxygen and nitrogen species. We identify areas of additional research to address the integration of regulatory processes under altered physiological and pathophysiological conditions that may reveal insights into novel treatment strategies for conditions in which the matching of coronary blood supply and myocardial oxygen demand is compromised.
Dwenger Marc M; Ohanyan Vahagn; Navedo Manuel F; Nystoriak Matthew A
Microcirculation (New York, N.Y. : 1994)
2018
2018-01
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<a href="http://doi.org/10.1111/micc.12426" target="_blank" rel="noreferrer noopener">10.1111/micc.12426</a>
Deficiency of cholesterol 7alpha-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice.
Alcoholic fatty liver disease (AFLD) is a major risk factor for cirrhosis-associated liver diseases. Studies demonstrate that alcohol increases serum bile acids in humans and rodents. AFLD has been linked to cholestasis, although the physiologic relevance of increased bile acids in AFLD and the underlying mechanism of increasing the bile acid pool by alcohol feeding are still unclear. In this study, we used mouse models either deficient of or overexpressing cholesterol 7alpha-hydroxylase (Cyp7a1), the rate-limiting and key regulatory enzyme in bile acid synthesis, to study the effect of alcohol drinking in liver metabolism and inflammation. Mice were challenged with chronic ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight). Alcohol feeding reduced bile acid synthesis gene expression but increased the bile acid pool size, hepatic triglycerides and cholesterol, and inflammation and injury in wild-type mice and aggravated liver inflammation and injury in Cyp7a1-deficient mice. Interestingly, alcohol-induced hepatic inflammation and injury were ameliorated in Cyp7a1 transgenic mice. Conclusion: Alcohol feeding alters hepatic bile acid and cholesterol metabolism to cause liver inflammation and injury, while maintenance of bile acid and cholesterol homeostasis protect against alcohol-induced hepatic inflammation and injury. Our findings indicate that CYP7A1 plays a key role in protection against alcohol-induced steatohepatitis. (Hepatology Communications 2018;2:99-112).
Donepudi Ajay C; Ferrell Jessica M; Boehme Shannon; Choi Hueng-Sik; Chiang John Y L
Hepatology communications
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep4.1129" target="_blank" rel="noreferrer noopener">10.1002/hep4.1129</a>
Epigenetic regulation in diabetes-associated oxidative stress and myocardial dysfunction.
*Epigenesis; *Oxidative Stress; Cardiomyopathies; Genetic; Humans
Yin Liya; Chilian William M; Dong Feng
International journal of cardiology
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijcard.2018.05.058" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2018.05.058</a>
Form follows function: polymorphisms in mAKAP alter cardiac cAMP/PKA signaling.
Paruchuri Sailaja; Thodeti Charles K
American journal of physiology. Heart and circulatory physiology
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00248.2018" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00248.2018</a>
Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the
Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L
Hepatology (Baltimore, Md.)
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.29857" target="_blank" rel="noreferrer noopener">10.1002/hep.29857</a>
Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Male; Animals; Mice; Random Allocation; Sensitivity and Specificity; *Signal Transduction; Lipid Metabolism; Bile Acids and Salts/*metabolism; GTP-Binding Proteins/*metabolism; Receptors; Inbred C57BL; Animal; Disease Models; G-Protein-Coupled/*metabolism; Gastrointestinal Microbiome/*drug effects; Glucagon-Like Peptide 1/metabolism; Cytoplasmic and Nuclear/*antagonists & inhibitors/pharmacology
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the
Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L
Hepatology (Baltimore, Md.)
2018
2018-10
<a href="http://doi.org/10.1002/hep.29857" target="_blank" rel="noreferrer noopener">10.1002/hep.29857</a>
Mitochondrial complex I in the post-ischemic heart: reperfusion-mediated oxidative injury and protein cysteine sulfonation.
Complex I; Mitochondrial dysfunction; Myocardial ischemia and reperfusion; Protein cysteine sulfonation; Protein structure
A serious consequence of ischemia-reperfusion injury (I/R) is oxidative damage leading to mitochondrial dysfunction. Such I/R-induced mitochondrial dysfunction is observed as impaired state 3 respiration and overproduction of O2(-). The cascading ROS can propagate cysteine oxidation on mitochondrial complex I and add insult to injury. Herein we employed LC-MS/MS to identify protein sulfonation of complex I in mitochondria from the infarct region of rat hearts subjected to
Kang Patrick T; Chen Chwen-Lih; Lin Paul; Zhang Liwen; Zweier Jay L; Chen Yeong-Renn
Journal of molecular and cellular cardiology
2018
2018-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.yjmcc.2018.07.244" target="_blank" rel="noreferrer noopener">10.1016/j.yjmcc.2018.07.244</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
*Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon-Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
Humans; Male; Animals; Mice; *Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5; Diet; Hep G2 Cells; Receptors; Inbred C57BL; High-Fat/adverse effects; Cytoplasmic and Nuclear/*agonists; Bile Acids and Salts/pharmacology/*therapeutic use; Hypercholesterolemia/*drug therapy/etiology/metabolism; Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/metabolism; Obesity/*drug therapy/etiology/metabolism; G-Protein-Coupled/*agonists
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes.
Cardiac; Cell therapy; Diabetes; Stem cells; Stromal derived factor-1
Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF-1:CXCR4 expression is compromised in post-AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell-derived factor-1 (SDF-1). SDF-1 expression in control MSC and SDF-1-overexpressing MSC (SDF-1:MSC) were quantified using enzyme-linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF-1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF-1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF-1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post-AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post-AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF-1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The
Mayorga Maritza E; Kiedrowski Matthew; McCallinhart Patricia; Forudi Farhad; Ockunzzi Jeremiah; Weber Kristal; Chilian William; Penn Marc S; Dong Feng
Stem cells translational medicine
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/sctm.17-0172" target="_blank" rel="noreferrer noopener">10.1002/sctm.17-0172</a>
Sonic Hedgehog Signaling Regulates Hematopoietic Stem/Progenitor Cell Activation during the Granulopoietic Response to Systemic Bacterial Infection.
*bacterial infection; *hedgehog signaling; *hematopoietic stem cells; *progenitor cells; *the granulopoietic response
Activation and reprogramming of hematopoietic stem/progenitor cells play a critical role in the granulopoietic response to bacterial infection. Our current study determined the significance of Sonic hedgehog (SHH) signaling in the regulation of hematopoietic precursor cell activity during the host defense response to systemic bacterial infection. Bacteremia was induced in male Balb/c mice via intravenous injection (i.v.) of Escherichia coli (5 x 10(7) CFUs/mouse). Control mice received i.v. saline. SHH protein level in bone marrow cell (BMC) lysates was markedly increased at both 24 and 48 h of bacteremia. By contrast, the amount of soluble SHH ligand in marrow elutes was significantly reduced. These contrasting alterations suggested that SHH ligand release from BMCs was reduced and/or binding of soluble SHH ligand to BMCs was enhanced. At both 12 and 24 h of bacteremia, SHH mRNA expression by BMCs was significantly upregulated. This upregulation of SHH mRNA expression was followed by a marked increase in SHH protein expression in BMCs. Activation of the ERK1/2-SP1 pathway was involved in mediating the upregulation of SHH gene expression. The major cell type showing the enhancement of SHH expression in the bone marrow was lineage positive cells. Gli1 positioned downstream of the SHH receptor activation serves as a key component of the hedgehog (HH) pathway. Primitive hematopoietic precursor cells exhibited the highest level of baseline Gli1 expression, suggesting that they were active cells responding to SHH ligand stimulation. Along with the increased expression of SHH in the bone marrow, expression of Gli1 by marrow cells was significantly upregulated at both mRNA and protein levels following bacteremia. This enhancement of Gli1 expression was correlated with activation of hematopoietic stem/progenitor cell proliferation. Mice with Gli1 gene deletion showed attenuation in activation of marrow hematopoietic stem/progenitor cell proliferation and inhibition of increase in blood granulocytes following bacteremia. Our results indicate that SHH signaling is critically important in the regulation of hematopoietic stem/progenitor cell activation and reprogramming during the granulopoietic response to serious bacterial infection.
Shi Xin; Wei Shengcai; Simms Kevin J; Cumpston Devan N; Ewing Thomas J; Zhang Ping
Frontiers in immunology
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fimmu.2018.00349" target="_blank" rel="noreferrer noopener">10.3389/fimmu.2018.00349</a>
The coronary circulation in acute myocardial ischaemia/reperfusion injury - a target for cardioprotection.
The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolisation of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leukocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction and intramyocardial haemorrhage. Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. Microvascular obstruction and intramyocardial haemorrhage can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
Hausenloy Derek J; Chilian William; Crea Filippo; Davidson Sean M; Ferdinandy Peter; Garcia-Dorado David; van Royen Niels; Schulz Rainer; Heusch Gerd
Cardiovascular research
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/cvr/cvy286" target="_blank" rel="noreferrer noopener">10.1093/cvr/cvy286</a>
The gut's feeling on bile acid signaling in NAFLD.
Chiang John Y L
Hepatobiliary surgery and nutrition
2018
2018-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.21037/hbsn.2018.01.02" target="_blank" rel="noreferrer noopener">10.21037/hbsn.2018.01.02</a>