Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

Nitti, Mariapaola; Furfaro, Anna Lisa; Mann, Giovanni E.

doi:10.3389/fphys.2020.00023

Cited by 33 publications

(37 citation statements)

References 185 publications

(219 reference statements)

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“…One of the best-known examples of Nrf2-regulated gene is Ho-1 that, once induced via the Nfr2/Mafg activity, cleaves heme into biliverdin, which is in turn rapidly converted to bilirubin, carbon monoxide (CO) and ferrous iron (Fe 2+ ) [ 53 ]. Since we have found a strong enrichment of Ho-1 mRNA and protein in the skeletal muscle of fasted mice ( Figure 2 b,d), we hypothesized that skeletal muscle responses to nutrient stress could involve the induction of iron-scavenging mechanisms in order to avoid free iron overload and thus prevent possible lipid peroxidation.…”

Section: Resultsmentioning

confidence: 99%

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

Lettieri-Barbato

Minopoli

Caggiano

et al. 2020

IJMS

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A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle.

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Section: Resultsmentioning

confidence: 99%

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

Lettieri-Barbato

Minopoli

Caggiano

et al. 2020

IJMS

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“…Furthermore, SMCs isolated from HO-1-deficient mice exhibit greater rates of cell growth relative to cells derived from wild-type animals. Moreover, induction of HO-1 by many endogenous factors and pharmaceutical compounds blocks the proliferation of vascular SMCs [10][11][12][13][14][15][16][17][18]. The inhibition of SMC growth by HO-1 is associated with an increase in p21 expression and the arrest of SMCs in the G 0 /G 1 phase of the cell cycle, whereas inhibition of HO-1 activity promotes cell cycle progression [34,35].…”

Section: Effect Of Ho-1 On Vascular Smc Functionmentioning

confidence: 99%

“…As previously reviewed [10][11][12][13][14][15][16][17][18]149], many vanguard drugs used to treat cardiovascular disease stimulate the expression of HO-1, including statins, aspirin, nitrates, sildenafil, rapamycin, and paclitaxel. Furthermore, the induction of HO-1 by these drugs is speculated to contribute to their clinical efficacy.…”

Section: Therapeutic Potential Of Ho-1 and Its Products In Vascular Rmentioning

confidence: 99%

“…Given the important contribution of vascular SMCs to arterial remodeling, the targeting of these cells offers a possible strategy for therapeutic intervention. Accumulating evidence over the past three decades has identified the enzyme heme oxygenase-1 (HO-1) as a critical regulator of cardiovascular health and disease [10][11][12][13][14][15][16][17][18]. Diverse mechanisms appear to mediate the protective actions of HO-1 in the circulation, including anti-inflammatory and antioxidant effects; anti-thrombotic actions; inhibition of vasomotor tone; and its ability to modulate the growth, function, and survival of vascular cells.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

Durante¹

2020

Antioxidants

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.

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“…Heme oxygenase is the first, rate-limiting enzyme in heme degradation pathway, with two major isoforms of heme oxygenase identified. First Heme oxygenase-1 is inducible whereas, expressed only under oxidative stress or when heme oxygenase-2 [38,39].…”

Section: Bilirubin and Heme Oxygenasesmentioning

confidence: 99%

Bilirubin metabolism and its role in atherosclerosis

Yılmaz

Mun˜oz

Eren

et al. 2020

Archives of Clinical and Experimental Medicine

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Hemoglobin is not an guiltless bystander of the pathophysiology in a number of atherosclerotic diseases. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as intracellular stress. Although heme serves key functions and is tightly controlled, high levels of free heme, which may occur in various pathophysiological conditions, are may hazardous via pro-oxidant, pro-inflammatory, and cytotoxic effects. Heme oxygenases are heat shock protein enzymes that use heme as a substrate and function as an essential antioxidant adaptive response by all human cells. A major function of heme oxygenases is clearance of heme that accumulate in tissues due to erythrocyte turnover. The potentially toxic free heme is converted by heme oxygenases into carbon monoxide, iron, and biliverdin, the third of which is reduced to bilirubin. In literature the heme degradation pathway has been demonstrated to play a protective role against the development of atherosclerosis. Because growing evidence suggests that oxidative stress is involved in atherosclerosis. This review documents the roles of bilurubin in atherosclerosis and focuses on the clinical significance as a potential therapeutic target in atherosclerotic diseases, such as coronary artery disease.

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Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

Cited by 33 publications

References 185 publications

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

Bilirubin metabolism and its role in atherosclerosis

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