Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

Kusmic, Claudia; Barsanti, Cristina; Matteucci, Marco; Vesentini, Nicoletta; Pelosi, Gualtiero; Abraham, Nader G.; LʼAbbate, Antonio

doi:10.1186/1479-5876-12-89

Cited by 24 publications

(20 citation statements)

References 49 publications

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“…45). Furthermore, its protective effects have been extensively described in diverse forms of extra-renal tissue damage (e.g., brain, liver, heart, organ transplantation) (46–52). However, less certain than the existence of HO’s protective actions is the exact mechanism by which that protection is effected.…”

Section: Discussionmentioning

confidence: 99%

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Zager

2015

Translational Research

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The phenomenon of so called renal “ischemic preconditioning”, whereby an initial ischemic insult induces resistance against subsequent kidney damage, has been well established in the experimental literature. However, a clinically applicable way to safely recapitulate this state has not been defined. We hypothesized that a unique combination of agents (nitrited myoglobin + Sn protoporphyrin) can achieve these ends by safely, and synergistically, increasing cytoprotective proteins (e.g., HO-1, IL-10, haptoglobin) in kidney cells. To test this hypothesis, CD-1 mice received 1 mg N-Mgb and 1 µmole SnPP, either alone or in combination. Renal cortical HO-1, haptoglobin, and IL-10 gene expression (mRNA, protein levels) were determined 4 and 18 hrs later. Cytoresistance to three forms of AKI were assessed (glycerol- induced rhabdomyolysis; maleate nephrotoxicity; post-ischemic AKI progression to CKD). To ascertain whether cytoresistance might emerge in extra-renal organs, hepatic HO-1, IL-10, and haptoglobin levels were also measured, and resistance to 25 min of hepatic ischemia-reperfusion injury and hepatotoxicity (intraperitoneal glycerol injection) was sought. N-Mgb + SnPP induced additive or synergistic increases in renal HO-1, haptoglobin, and IL-10 mRNA/protein levels (up to 20 fold) without inducing any apparent renal or extra-renal damage. By 18 hrs post treatment, marked, or complete, protection against glycerol-induced AKI, maleate- induced AKI, and post ischemic AKI progression to CKD had emerged. Combined N-Mgb+SnPP was more protective than was either agent alone (assessed in glycerol model). N-Mgb+SnPP also up-regulated cytoprotective pathways in liver, and induced marked protection against both hepatic ischemia-reperfusion and toxic liver damage. In sum, we posit that “preconditioning” with combined N-Mgb+SnPP administration represents a promising approach for protecting against diverse forms of renal and non renal (hepatic) forms of tissue damage.

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Section: Discussionmentioning

confidence: 99%

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Zager

2015

Translational Research

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“…Tissue samples were sectioned at a thickness of 5 μm [26]. In each lung section, 30 small PAs (50–100 μm in diameter) were analysed at × 40 in a blinded manner.…”

Section: Methodsmentioning

confidence: 99%

Role of P2X7R in the development and progression of pulmonary hypertension

et al. 2017

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BackgroundPulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X7 receptor (P2X7R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH.Methods and resultsPH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness. Marked P2X7R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X7R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X7 receptor antagonist, 30 mg/kg) daily starting from 1 week before or 2 weeks after MCT injection. Consequently, A-740003 reversed the NLRP3 inflammasome upregulation, significantly decreased the mean right ventricular (RV) pressure and RV hypertrophy, and reversed pulmonary arterial remodelling 4 weeks after MCT injection, as both a pretreatment and rescue intervention. Notably, A-740003 significantly reduced macrophage and pro-inflammatory cytokine levels, as measured via bronchoalveolar lavage. The recruitment of macrophages as well as collagen fibre deposition in the perivascular areas were also reduced, as confirmed by histological staining.ConclusionsP2X7R contributes to the pathogenesis of PH, probably in association with activation of the NLRP3 inflammasome. Blockade of P2X7R might be applied as a novel therapeutic approach for the treatment of PAH.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0603-0) contains supplementary material, which is available to authorized users.

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“…The former indicates a comparable entity of the ischemic damage in rats subjected to I/R procedure (36). The latter defines the framework of the preclinical Low-T3S model (31).…”

Section: Inclusion Criteriamentioning

confidence: 99%

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

Nicolini

Forini

Kusmic

et al. 2015

Mol Med

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Activation of transforming growth factor (TGF)-β1 signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30-133, favoring the profibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the postischemic low-T3 syndrome (Low-T3S) exerts antifibrotic effects, but the underlying molecular players are still unknown. Here we hypothesize that a prompt, short-term infusion of T3 in a rat model of post I/R Low-T3S could hamper the early activation of the TGFβ1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR. Twenty-four hours after I/R, rats that developed the Low-T3S were randomly assigned to receive a 48-h infusion of 6 μg/kg/d T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3 or 14 d post-I/R. Three days post-I/R, Low-T3S correction favored functional cardiac recovery. This effect was paralleled by a drop in TGFβ1 and increased miR-133a, miR-30c and miR-29c in the infarcted myocardium. Consistently, connective transforming growth factor (CTGF) and matrix metalloproteinase-2 (MMP-2), validated targets of the above miRNAs, were significantly reduced. Fourteen days post-I/R, the I/R-L+T3 rats presented a significant reduction of scar size with a better preservation of cardiac performance and LV chamber geometry. At this time, TGFβ1 and miR-29c levels were in the normal range in both groups, whereas miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group. In conclusion, the antifibrotic effect exerted by T3 in the early phase of postischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and adverse CR.

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Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

Cited by 24 publications

References 49 publications

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Role of P2X7R in the development and progression of pulmonary hypertension

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling

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