Cardiac-Specific Expression of Heme Oxygenase-1 Protects Against Ischemia and Reperfusion Injury in Transgenic Mice

Yet, Shaw Fang; Tian, Rong; Layne, Matthew D.; Wang, Zhi Yuan; Maemura, Koji; Solovyeva, Maria; Ith, Bonna; Melo, Luis G.; Zhang, Lunan; Ingwall, Joanne S.; Dzau, Victor J.; Lee, Mu En; Perrella, Mark A.

doi:10.1161/hh1401.093314

Cited by 384 publications

(299 citation statements)

References 45 publications

(41 reference statements)

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“…Some of these changes have been reported in the case of ischemic preconditioning for Cox2 and Por (Shinmura et al 2002) as well as for HO-1 (Yet et al 2001), and in the case of mild training for GPX2 (Chicco et al 2006).…”

Section: Discussionmentioning

confidence: 86%

Mild exercise training, cardioprotection and stress genes profile

et al. 2007

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To improve current knowledge of the molecular mechanisms underlying exercise-induced cardioprotection in a rat model of mild exercise training, Sprague-Dawley rats were trained to run on a treadmill up to 55% of their maximal oxygen uptake for 1 h/day, 3 days/week, 14 weeks, with age-matched sedentary controls (n = 20/group). Rats were sacriWced 48 h after the last training session. Despite lack of cardiac hypertrophy, training decreased blood hemoglobin (7.94 § 0.21 mM vs. 8.78 § 0.23 mM, mean § SE, P = 0.01) and increased both plasma malondialdehyde (0.139 § 0.005 mM vs. 0.085 § 0.009 mM, P = 0.05) and the activity of Mn-superoxide dismutase (11.6 § 0.6 vs. 16.5 § 1.6 mU/ g, P = 0.01), whereas total superoxide dismutase activity was unaVected. When subjected to 30-min ischemia followed by 90-min reperfusion, hearts from trained rats (n = 5) displayed reduced infarct size as compared to controls (37.26 § 0.92% vs. 49.09 § 2.11% of risk area, P = 0.04). The biochemical analyses in the myocardium, which included gene expression proWles, realtime PCR, Western blot and determination of enzymatic activity, showed training-induced upregulation of the following mRNAs and/or proteins: growtharrest and DNA-damage induced 153 (GADD153/ CHOP), heme-oxygenase-1 (HO-1), cyclooxygenase-2 (Cox-2), heat-shock protein 70/72 (HSP70/72), whereas heat-shock protein 60 (HSP60) and glucoseregulated protein 75 (GRP75) were decreased. As a whole, these data indicate that mild exercise training activates a second window of myocardial protection against ischemia/reperfusion by upregulating a number of protective genes, thereby warranting further investigation in man.

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Section: Discussionmentioning

confidence: 86%

Mild exercise training, cardioprotection and stress genes profile

et al. 2007

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“…The enzyme is induced several fold by hypoxia and reoxygenation [28,29], and genetic mouse models of HO-1 deficiency have greater propensity towards ischemia and hyperoxia induced tissue injury [12,13]. Moreover, pre-emptive delivery of HO-1 gene markedly reduces infarct size following acute I/R [10,11], suggesting that enhanced basal level of HO-1 preconditions the myocardium [12,30] and renders it resistant to subsequent episodes of I/R injury [14]. Thus, strategies aimed at increasing basal HO-1 levels may yield therapeutic potential in protection against I/R induced myocardial injury and failure.…”

Section: Discussionmentioning

confidence: 99%

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent in various models of ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1 induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1 derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo. H9c2 cardiomyocytes were transfected with a plasmid expressing HO-1 or LacZ and exposed to 24 hours of hypoxia followed by 12 hours of reoxygenation. At the end of reoxygenation, reactive oxygen species generation was determined using CM-H 2 DCFDA dye and apoptosis was assessed by TUNEL, caspase activity and Bad phosphorylation. p85 and Akt phosphorylation were determined using cell based ELISA and phospho-specific antibodies, respectively. HO-1 overexpression increased phosphorylation of the regulatory subunit of the PI3K (p85α) and downstream effector Akt in H9c2 cells, leading to decreased ROS and apoptosis. Furthermore, cardiac specific HO-1 expression increased basal phosphorylated Akt levels and decreased infarct size in response to LAD ligation and release induced I/R injury. Conversely, PI3K inhibition reversed the effects of HO-1 on Akt phosphorylation, cell death and infarct size. In addition, knockdown of biliverdin reductase (BVR) expression with siRNA attenuated HO-1 induced Akt phosphorylation and increased H/R-induced apoptosis of H9c2 cells. Co-immunoprecipitation revealed protein-protein interaction between BVR and the phosphorylated p85 subunit of the PI3 kinase. Taken together, these results suggest that the enzyme biliverdin reductase plays an important role in mediating cytoprotective effects of HO-1. This effect is mediated, at least in part, via activation of the PI3K/Akt pathway.

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“…We obtained [5,6,8,11,12,14,15(N)-3 H]-prostaglandin E 2 (PGE 2 ) from Amersham Biosciences (Barcelona, Spain). Cyclooxygenase 2 (COX-2)-specific polyclonal antibody was purchased from Cayman Chemical (Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

“…In inflammatory and immune conditions, high levels of mediators with the potential to induce HO-1 are produced, and the expression of this protein could be part of an adaptive mechanism for limiting cytotoxicity via several means, including radical scavenging or inhibition of cell proliferation and apoptosis (9,10). The beneficial effects of HO-1 overexpression have been shown in a number of conditions, such as endotoxemia (11), lung hyperoxia (12), atherogenesis (13), myocardial injury after ischemiareperfusion (14), and cardiac allograft survival (15). HO-1 induction has also been shown to down-regulate the inflammatory response in animal models of acute inflammation.…”

mentioning

confidence: 99%

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

Devesa¹,

Ferrándiz²,

Terencio³

et al. 2005

Arthritis & Rheumatism

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Objective. Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.Methods. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E 2 (PGE 2 ) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.Results. CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor ␣ (TNF␣), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE 2 , IL-1␤, and TNF␣ were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).Conclusion. HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.

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Cardiac-Specific Expression of Heme Oxygenase-1 Protects Against Ischemia and Reperfusion Injury in Transgenic Mice

Cited by 384 publications

References 45 publications

Mild exercise training, cardioprotection and stress genes profile

Mild exercise training, cardioprotection and stress genes profile

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

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