Heme Oxygenase Improves Renal Function by Potentiating Podocyte-Associated Proteins in <i>N</i>ω-Nitro-<scp>l</scp>-Arginine-Methyl Ester (<scp>l</scp>-NAME)-Induced Hypertension

Ndisang, Joseph Fomusi; Chibbar, Rajni

doi:10.1093/ajh/hpu240

Cited by 12 publications

(11 citation statements)

References 36 publications

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“…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. Thus, we reasoned information affording a greater understanding of the cellular and molecular framework of the HO-1 -adiponectin axis would help to identify, validate and progress development of efficacious therapeutic approaches.…”

Section: Discussionmentioning

confidence: 85%

“…In contrast, the majority of preclinical studies suggest that induction of HO-1 increases adiponectin production and improves metabolic status via a "HO-1 -adiponectin axis" [217,225,227,230,239,241,[264][265][266][267][268]. To test this ourselves, we performed a series of experiments in preclinical models.…”

Section: General Discussion and Further Directionsmentioning

confidence: 99%

“…A recent study also showed that MC4R-deficient obese mice treated with long-term (4-23 weeks of age) CoPP administration, exhibited increased oxygen consumption, and CO2 and heat production [224]. Increased adiponectin has also been reported and has been proposed to underpin these beneficial effects [209,[225][226][227][228]. Studies have also shown that the above benefits can be reversed by SnMP treatment [210,217].…”

Section: Ho-1 and Obesitymentioning

confidence: 95%

“…Heme Oxygenase-1 is a rate-limiting enzyme that catalysts the degradation of heme into three by-products, carbon monoxide (CO), iron and biliverdin, which is subsequently converted to bilirubin [261]. In preclinical models, induction of HO-1 has been reported to increase circulating adiponectin levels, concomitant with a decrease in inflammatory cytokines, prompting the proposal of a "HO-1 -adiponectin axis" [217,225,227,230,239,241,[264][265][266][267][268]. However, contradictory findings showed that a classic transgenic approach to increased HO-1 in adipose tissue failed to reverse the HFD-induced decrease in adiponectin [281].…”

Section: Overviewmentioning

confidence: 99%

“…Accumulating evidence has led to the suggestion that HO-1 may mediate at least some of its beneficial effects by increasing circulating adiponectin levels through what has been termed the "HO-1 -adiponectin axis" [217,225,227,230,239,241,[264][265][266][267][268]. For example, chronic administration of obese mice with the HO-1 inducer cobalt protoporphyrin (CoPP) was reported to increase HO-1 protein, prevent weight gain and decrease fat content (in the absence of any change in food intake), reduce circulating inflammatory cytokines (including TNFα and IL-6) and increase circulating adiponectin levels [217].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 85%

Section: General Discussion and Further Directionsmentioning

confidence: 99%

Section: Ho-1 and Obesitymentioning

confidence: 95%

Section: Overviewmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yang¹

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The Different Facets of Dyslipidemia and Hypertension in Atherosclerosis

Hurtubise

McLellan

Durr

et al. 2016

Curr Atheroscler Rep

182

118

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Atherosclerosis is the narrowing of arteries due to the accumulation of macrophages overloaded with lipids resulting in foam cell formation, and these events occur preferentially at the branching points of arteries which are particularly susceptible to hyperlipidemic stress-induced inflammation and oxidative stress. The different stages of atherogenesis rely on oxidative stress, endothelial dysfunction, and inflammation, and hypertension or dyslipidemia can independently trigger these stages. Dyslipidemia and hypertension are pathological conditions that damage the endothelium, triggering cell proliferation, vascular remodeling, apoptosis, and increased cellular permeability with increased adhesion molecules that bind monocytes and T lymphocytes to create a vicious cocktail of pathophysiological factors. Correspondingly, the factors are redirected by chemo-attractants and pro-inflammatory cytokines into the intima of the vasculature, where monocytes differentiate into macrophages taking up oxidized LDL uncontrollably to form foam cells and atherosclerotic lesions. Moreover, endothelial damage also causes loss of vasomotor activity, disproportionate vascular contractility, and elevation of blood pressure in dyslipidemic patients, while in hypertensive patients, further elevation of blood pressure occurs, creating a self-perpetuating vicious cycle that aggravates the development and progression of atherosclerotic lesions. This review offers an in-depth analysis of atherosclerosis and the related interplay between dyslipidemia/hypertension and critically appraises the current diagnosis, etiology, and therapeutic options.

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