Critical Roles of Carbon Monoxide and Nitric Oxide in Ca<sup>2+</sup>Signaling for Insulin Secretion in Pancreatic Islets

Rahman, Faiz; Park, Dae-Ryoung; Joe, Yeonsoo; Jang, Kyu Yun; Chung, Hun Taeg; Kim, Uh-Hyun

doi:10.1089/ars.2017.7380

Cited by 17 publications

(10 citation statements)

References 66 publications

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“…It was demonstrated in pancreatic islets that CO activates CD38 through the activation of sGC. 54 Nevertheless, in platelets CO released from CORMs does not act through sGC (see Refs 11 , 12 and Figure IV in the Data Supplement ) making CO/cGMP/CD38 pathway unlikely to operate in platelets.…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion

Kaczara

Sitek

Przyborowski

et al. 2020

ATVB

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Objectives: Carbon monoxide (CO) produced by haem oxygenases or released by CO releasing molecules (CORM) affords antiplatelet effects, but the mechanism involved has not been defined. Here, we tested the hypothesis that CO–induced inhibition of human platelet aggregation is mediated by modulation of platelet bioenergetics. Approach and Results: To analyze the effects of CORM-A1 on human platelet aggregation and bioenergetics, a light transmission aggregometry, Seahorse XFe technique and liquid chromatography tandem-mass spectrometry–based metabolomics were used. CORM-A1–induced inhibition of platelet aggregation was accompanied by the inhibition of mitochondrial respiration and glycolysis. Interestingly, specific inhibitors of these processes applied individually, in contrast to combined treatment, did not inhibit platelet aggregation considerably. A CORM-A1–induced delay of Krebs cycle was associated with oxidized nicotinamide adenine dinucleotide (NAD + ) depletion, compatible with the inhibition of oxidative phosphorylation. CORM-A1 provoked an increase in concentrations of proximal (before GAPDH), but not distal glycolysis metabolites, suggesting that CO delayed glycolysis at the level of NAD + –dependent GAPDH; however, GAPDH activity was directly not inhibited. In the presence of exogenous pyruvate, CORM-A1–induced inhibition of platelet aggregation and glycolysis were lost, but were restored by the inhibition of lactate dehydrogenase, involved in cytosolic NAD + regeneration, pointing out to the key role of NAD + depletion in the inhibition of platelet bioenergetics by CORM-A1. Conclusions: The antiplatelet effect of CO is mediated by inhibition of mitochondrial respiration—attributed to the inhibition of cytochrome c oxidase, and inhibition of glycolysis—ascribed to cytosolic NAD+ depletion.

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Section: Discussionmentioning

confidence: 99%

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion

Kaczara

Sitek

Przyborowski

et al. 2020

ATVB

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“…Early studies implicated nitric oxide as the effector molecule responsible for the detrimental effects of proinflammatory cytokines on β-cell function (55,56). The role of nitric oxide in β-cell pathophysiology has been investigated over the years, and recent findings suggest its dual role as a molecule that inhibits insulin secretion but also as an activator of protective pathways, which protects β cells from damage (57,58). Our results demonstrated that overexpression of galectin 3 is related to increased levels of nitrite oxide, which is followed by its deleterious effects on β cells (Figure 5).…”

Section: Discussionmentioning

confidence: 55%

Overexpression of Galectin 3 in Pancreatic β Cells Amplifies β-Cell Apoptosis and Islet Inflammation in Type-2 Diabetes in Mice

et al. 2020

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Aims/Hypothesis: Galectin 3 appears to play a proinflammatory role in several inflammatory and autoimmune diseases. Also, there is evidence that galectin 3 plays a role in both type-1 and type-2 diabetes. During obesity, hematopoietic cell-derived galectin 3 induces insulin resistance. While the role of galectin 3 expressed in islet-invading immune cells in both type-1 and type-2 diabetes has been studied, the importance of the expression of this molecule on the target pancreatic β cells has not been defined. Methods:To clarify the role of galectin 3 expression in β cells during obesity-induced diabetogenesis, we developed transgenic mice selectively overexpressing galectin 3 in β cells and tested their susceptibility to obesity-induced type-2 diabetes. Obesity was induced with a 16-week high-fat diet regime. Pancreatic β cells were tested for susceptibility to apoptosis induced by non-esterified fatty acids and cytokines as well as parameters of oxidative stress.Results: Our results demonstrated that overexpression of galectin 3 increases β-cell apoptosis in HFD conditions and increases the percentage of proinflammatory F4/80 + macrophages in islets that express galectin 3 and TLR4. In isolated islets, we have shown that galectin 3 overexpression increases cytokine and palmitate-triggered β-cell apoptosis and also increases NO 2− -induced oxidative stress of β cells. Also, in pancreatic lymph nodes, macrophages were shifted toward a proinflammatory TNF-α-producing phenotype.Conclusions/Interpretation: By complementary in vivo and in vitro approaches, we have shown that galectin 3-overexpression facilitates β-cell damage, enhances cytokine and palmitate-triggered β-cell apoptosis, and increases NO 2− -induced oxidative stress in β cells. Further, the results suggest that increased expression of galectin 3 in the pancreatic β cells affects the metabolism of glucose and glycoregulation in mice on a high-fat diet, affecting both fasting glycemic values and glycemia after glucose loading.

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“…Potential toxicity of the free iron released by this reaction is prevented by its sequestration by ferritin, a physiological regulator of iron levels – and biliverdin is subsequently converted by biliverdin reductase to bilirubin, a potent endogenous antioxidant, which contributes substantially to control of inflammation by inhibition of NADPH oxidase [ 15 ]. CO is produced by this reaction at levels in which it acts as a highly efficient second messenger that augments cellular resistance to oxidative stress by increasing intracellular cyclic nucleotides, particularly cGMP, according to the general reaction: CO-> guanylate cyclase ->increased cGMP [ 16 ]. These HO-mediated processes additionally stabilize membrane ionic balance preventing mitochondrial calcium overload-induced tissue damage [ 17 ].…”

Section: Heme Oxygenases: Major Physiological Activitiesmentioning

confidence: 99%

Role of Heme Oxygenases in Cardiovascular Syndromes and Co-morbidities

Haines

Tósaki

2018

CPD

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Cardiovascular Diseases (CVD), are the leading cause of human mortality worldwide and the focus of the intensive investigation is to characterize their pathogenesis. This review examines contribu-tion to CVD of heme oxygenases (HOs), heat shock protein enzymes, comprising 3 isoforms: HO-1 (inducible), HO-2 (constitutively expressed) and HO-3 (function presently undefined), which constitute a primary endogenous countermeasure to oxidative tissue damage. Their role as CVD countermeasures is considered in the context of atherosclerosis, consequences of which are the leading cause of CVD deaths and from which 5 major syndromes may develop, namely: coronary artery disease and stroke, peripheral artery disease, kidney disease, cardiopulmonary disease and cerebrovascular disease. Over 75% of CVD deaths result from Coronary artery disease and stroke, with the severity of these condi-tions correlating with a systemic increase of the endogenous antioxidant bilirubin, produced by HO degradation of heme. Peripheral artery disease, (PAD) resulting from constricted arteries of the extremi-ties is a painful and disabling condition, the severity of which correlates with elevated serum HO. Whether this represents an adaptive response or the enzyme is a contributor to PAD, remains to be de-termined. CVD symptoms, particularly hypertension, damage the vasculature and filtering structures of the kidneys and may be ameliorated by HO inducers. Interestingly, constitutive renal expression of HO-2 indicates that the enzyme is vital for healthy kidney function. Right ventricular hypertrophy and in-creased vascular resistance in blood vessels of the lungs exhibit mutually reinforcing positive feedback to result in cardiopulmonary heart disease, with morbidity and mortality resulting from associated in-flammation and may be decreased with HO-1 inducers. Cerebrovascular disease, a major CVD compli-cation affecting brain vasculature, with resulting susceptibility to stroke, maybe potently ameliorated by HO-1 inducers.Conclusion: Each of the six major categories of CVD exhibit features of pathogenesis that hold potential as future therapeutic targets, for modulated heme oxygenase activity.

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Critical Roles of Carbon Monoxide and Nitric Oxide in Ca²⁺Signaling for Insulin Secretion in Pancreatic Islets

Abstract: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca signaling messengers during insulin secretion in pancreatic β-cells. Antioxid. Redox Signal. 00, 000-000.

Cited by 17 publications

References 66 publications

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion

Overexpression of Galectin 3 in Pancreatic β Cells Amplifies β-Cell Apoptosis and Islet Inflammation in Type-2 Diabetes in Mice

Role of Heme Oxygenases in Cardiovascular Syndromes and Co-morbidities

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Critical Roles of Carbon Monoxide and Nitric Oxide in Ca2+Signaling for Insulin Secretion in Pancreatic Islets

Abstract: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca signaling messengers during insulin secretion in pancreatic β-cells. Antioxid. Redox Signal. 00, 000-000.

Cited by 17 publications

References 66 publications

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD + and ATP Depletion

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD + and ATP Depletion

Overexpression of Galectin 3 in Pancreatic β Cells Amplifies β-Cell Apoptosis and Islet Inflammation in Type-2 Diabetes in Mice

Role of Heme Oxygenases in Cardiovascular Syndromes and Co-morbidities

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Resources

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Critical Roles of Carbon Monoxide and Nitric Oxide in Ca²⁺Signaling for Insulin Secretion in Pancreatic Islets

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion

Antiplatelet Effect of Carbon Monoxide Is Mediated by NAD ⁺ and ATP Depletion