Cobalt-Protoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes

Cao, Jian; Vecoli, Cecilia; Neglia, Danilo; Tavazzi, Barbara; Lazzarino, Giuseppe; Novelli, Michela; Masiello, Pellegrino; Wang, Yu Tang; Puri, Nitin; Paolocci, Nazareno; LʼAbbate, Antonio; Abraham, Nader G.

doi:10.3389/fphys.2012.00160

Cited by 30 publications

(23 citation statements)

References 36 publications

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“…In the same models, pharmacological treatments able to restore the eNOS expression were also able to reduce coronary resistance, leading to improvement of cardiac function [18], [23]. Differences in the animal models employed may account for the apparent difference between previous and present results.…”

Section: Discussionmentioning

confidence: 60%

“…In previous studies we have reported an increased expression of iNOS in cardiac tissue in animal models of metabolic impairment and secondary reduction of eNOS expression [18], [22], [23]. Decreased levels of eNOS and augmented expression of iNOS, together with enhanced oxidative stress, have been implicated in the pathogenesis of abnormal coronary function and potential myocardial damage [34].…”

Section: Discussionmentioning

confidence: 95%

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Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

et al. 2014

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Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS−/− and eNOS+/− mice were studied. WT and eNOS+/− mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS−/−. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS−/−) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS−/− and eNOS+/− mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS−/−. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 95%

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

et al. 2014

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“…In animal models of myocardial ischemia (MI), both over-expression and pharmacological induction of HO-1 reduce infarct size and ventricular remodeling after ischemia reperfusion damage, by improving cardiac metabolism 15,20,21 . Increased HO-1 expression has a protective effect against ischemia reperfusion injury in the kidney, and can correct blood pressure elevation following Ang II exposure 15 .…”

Section: Introductionmentioning

confidence: 99%

HO-1 Induction Improves The Type-1 Cardiorenal Syndrome in Mice With Impaired Angiotensin II–Induced Lymphocyte Activation

Monu

Paterini²,

Sodhi³

et al. 2013

Hypertension

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Type-1 cardiorenal syndrome (CRS-1), characterized by acute kidney dysfunction secondary to cardiac failure and renal arteriolar vasoconstriction, is mediated by the renin-angiotensin-aldosterone axis and sympathetic nervous system activation. Previous reports indicate that AngII modulates immune function and causes recruitment and activation of T lymphocytes. The goal of this study was to evaluate the effects of post-ischemic heart failure on renal morphology and circulation and the beneficial effects of heme oxygenase (HO-1) induction in T- lymphocyte suppressed BALB SCID mice. Mice were divided in 4 groups: sham, myocardial infarction (MI), MI treated with an HO-1 inducer, cobalt protoporphyrin (CoPP), and with or without stannous mesoporphyrin (SnMP), an inhibitor of HO activity. Heart and kidney function were studied 30 days after surgery. Fractional area change was reduced 30 days after surgery in both the C57 and SCID MI-groups as compared to their respective controls (p<0.01). Renal pulsatility index and renal injury were increased in C57 and SCID MI groups compared to the sham group. HO-1 induction improved renal vasoconstriction as well as ameliorated renal injury in both the SCID and C57 MI groups (p<0.01). However, improvement was more evident in SCID mice. In addition, our results showed that plasma creatinine, Ang II and renin were significantly increased in the C57 and SCID MI groups as compared to their respective controls. HO-1 induction decreased these parameters in both MI groups. SnMP reversed the beneficial effect of CoPP in both mouse strains. The study demonstrates that T-lymphocyte suppression facilitated the HO-1 dependent improvement in the attenuation of CRS-1.

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“…Numerous reports have described an association between pharmacological induction of HO-1 and increased circulating levels of the beneficial adipokine adiponectin, in in vivo studies in rodents [217,225,227,[236][237][238][239][240][241][242], and in vitro studies, showing increased adiponectin secretion from adipocytes [238,242]. These observations stimulated the proposal of a HO-1 -adiponectin axis [217,225,227,230,239,241,[264][265][266][267][268] which could underpin, at least in part, the favourable effects of HO-1 induction reported in most pre-clinical models of obesity and related cardiometabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Adiponectin-deficient mice exhibit diet-induced obesity and insulin resistance [30] which can be reversed by adiponectin administration [31]. Therefore, it is thought that the increased levels of adiponectin are the mechanism by which induction of HO-1 results in improvement of the health status in obese subjects [217,225,227,[236][237][238][239][240][241][242]. These adipocytes usually produce a large amount of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL1-β, and a small amount of the beneficial adipokine, adiponectin.…”

Section: Ho-1 and Adipocytesmentioning

confidence: 99%

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Yang¹

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The prevalence of obesity is growing at an alarming rate worldwide, and current therapies have limited benefits. Therefore, it is essential to increase our understanding of the underlying mechanisms so that new strategies can be developed to reduce the incidence of obesity related diseases. Adiponectin is an adipocyte-derived hormone that regulates glucose and lipid metabolism via direct and indirect mechanisms and has anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. Hypoadiponectinemia is implicated in the aetiology of obesity-related diseases making strategies to increase circulating adiponectin levels therapeutically attractive.Emerging evidence, predominantly from preclinical studies, suggests induction of heme-oxygenase-1 (HO-1) increases adiponectin production concomitant with decreased inflammatory tone prompting the proposal of a "HO-1 -adiponectin axis." However, the underlying mechanisms of increased adiponectin production via HO-1 induction are poorly defined; indeed a direct relationship has not been demonstrated. Thus, the overarching aim of this thesis is to investigate the effects of HO-1 induction on adiponectin production as well as adipocyte and adipose tissue remodelling and metabolic parameters using cellular and mouse models.Initial studies were designed to characterize the direct effect of HO-1 induction on adiponectin production. We found that treatment with the widely used HO-1 inducer cobalt protoporphyrin (CoPP) or hemin for 24-48 h increased HO-1 expression and activity without affecting adiponectin expression and secretion, in human mature adipocyte under a variety of experimental scenarios.Treatment of adipocytes with TNFα reduced adiponectin production and induced pro-inflammatory cytokines production. HO-1 induction failed to reverse these effects. These results do not support a direct HO-1 -adiponectin axis.However, literature suggests that chronic induction of HO-1 via CoPP administration throughout differentiation, promotes adiponectin secretion, albeit in the context of reduced adipogenesis. While our previous findings argued against the existence of a direct "HO-1 -adiponectin axis," they did not address the potential effects of chronic induction of HO-1 on adiponectin production. Thus, we extended our study to characterise the effects of chronic HO-1 induction throughout differentiation of human preadipocytes. In this study we demonstrate that chronic induction of HO-1 with CoPP or hemin throughout differentiation results in dose-dependent inhibition of adipogenesis and adiponectin production as well as induction of additional NRF2 target genes. Co-treatment with SnMP (HO-1 activity inhibitor) and HO-1 siRNA did not prevent these effects. These findings suggest that the chronic treatment with CoPP or hemin inhibits adipogenesis and adiponectin production potentially by a HO-1-independent mechanism that may be downstream of NRF2.iii However, our results contradict the majority of reports in the literature. One possibility is that the ...

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Cobalt-Protoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes

Cited by 30 publications

References 36 publications

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

HO-1 Induction Improves The Type-1 Cardiorenal Syndrome in Mice With Impaired Angiotensin II–Induced Lymphocyte Activation

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

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