Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease

Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.

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Role of Heme Oxygenase-1 in the Regulation of Blood Pressure and Cardiac Function

Experimental Biology and Medicine ◽

10.1177/15353702-0322805-03 ◽

2003 ◽

Vol 228 (5) ◽

pp. 447-453 ◽

Cited By ~ 61

Author(s):

Yen-Hsu Chen ◽

Shaw-Fang Yet ◽

Mark A. Perrella

Keyword(s):

Blood Pressure ◽

Cardiac Function ◽

Reperfusion Injury ◽

Heme Oxygenase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Heme Oxygenase 1 ◽

Coronary Artery Ligation ◽

Regulation Of Blood Pressure

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article, we will review the role of HO-1 in the regulation of blood pressure and cardiac function and highlight previous studies from our laboratory using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, hypertension, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney–one clip surgery were more severe in HO-1-null mice. In addition, HO-1-null mice with endotoxemia had earlier resolution of hypotension, yet the mortality and the incidence of end-organ damage were higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 had an improvement in cardiac function, smaller myocardial infarctions, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, whereas overexpression of HO-1 plays a protective role in hypoperfusion and ischemia/reperfusion injury.

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A Dual Role of Heme Oxygenase-1 in Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20010039 ◽

2018 ◽

Vol 20 (1) ◽

pp. 39 ◽

Cited By ~ 48

Author(s):

Shih-Kai Chiang ◽

Shuen-Ei Chen ◽

Ling-Chu Chang

Keyword(s):

Cell Death ◽

Heme Oxygenase ◽

Cancer Progression ◽

Critical Role ◽

Causative Factor ◽

Protective Role ◽

Dark Side ◽

Heme Oxygenase 1 ◽

Cellular Iron

Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors.

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Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-08-0325 ◽

2009 ◽

Vol 7 (11) ◽

pp. 1745-1755 ◽

Cited By ~ 74

Author(s):

Geraldine Gueron ◽

Adriana De Siervi ◽

Mercedes Ferrando ◽

Marcelo Salierno ◽

Paola De Luca ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Heme Oxygenase ◽

Critical Role ◽

Heme Oxygenase 1 ◽

Prostate Cancer Cells ◽

Invasive Potential

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The Role of Heme Oxygenase-1 in Remote Ischemic and Anesthetic Organ Conditioning

Antioxidants ◽

10.3390/antiox8090403 ◽

2019 ◽

Vol 8 (9) ◽

pp. 403 ◽

Cited By ~ 4

Author(s):

Bauer ◽

Raupach

Keyword(s):

Heme Oxygenase ◽

Cell Damage ◽

Expression Patterns ◽

Organ Injury ◽

Heme Oxygenase 1 ◽

Causative Role ◽

Organ Protection ◽

Clinical Safety ◽

Ischemic Conditioning

The cytoprotective effects of the heme oxygenase (HO) pathway are widely acknowledged. These effects are mainly mediated by degradation of free, pro-oxidant heme and the generation of carbon monoxide (CO) and biliverdin. The underlying mechanisms of protection include anti-oxidant, anti-apoptotic, anti-inflammatory and vasodilatory properties. Upregulation of the inducible isoform HO-1 under stress conditions plays a crucial role in preventing or reducing cell damage. Therefore, modulation of the HO-1 system might provide an efficient strategy for organ protection. Pharmacological agents investigated in the context of organ conditioning include clinically used anesthetics and sedatives. A review from Hoetzel and Schmidt from 2010 nicely summarized the effects of anesthetics on HO-1 expression and their role in disease models. They concluded that HO-1 upregulation by anesthetics might prevent or at least reduce organ injury due to harmful stimuli. Due to its clinical safety, anesthetic conditioning might represent an attractive pharmacological tool for HO-1 modulation in patients. Remote ischemic conditioning (RIC), first described in 1993, represents a similar secure option to induce organ protection, especially in its non-invasive form. The efficacy of RIC has been intensively studied herein, including on patients. Studies on the role of RIC in influencing HO-1 expression to induce organ protection are emerging. In the first part of this review, recently published pre-clinical and clinical studies investigating the effects of anesthetics on HO-1 expression patterns, the underlying signaling pathways mediating modulation and its causative role in organ protection are summarized. The second part of this review sums up the effects of RIC.

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Selective Regulation of Blood Pressure by Heme Oxygenase-1 in Hypertension

Hypertension ◽

10.1161/01.hyp.0000028488.71068.16 ◽

2002 ◽

Vol 40 (3) ◽

pp. 315-321 ◽

Cited By ~ 75

Author(s):

Joseph Fomusi Ndisang ◽

Weimin Zhao ◽

Rui Wang

Keyword(s):

Blood Pressure ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Regulation Of Blood Pressure

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Critical Role of 5-Lipoxygenase and Heme Oxygenase-1 in Wound Healing

Journal of Investigative Dermatology ◽

10.1038/jid.2013.493 ◽

2014 ◽

Vol 134 (5) ◽

pp. 1436-1445 ◽

Cited By ~ 18

Author(s):

Ariane R. Brogliato ◽

Andrea N. Moor ◽

Shannon L. Kesl ◽

Rafael F. Guilherme ◽

Janaína L. Georgii ◽

...

Keyword(s):

Wound Healing ◽

Heme Oxygenase ◽

Critical Role ◽

Heme Oxygenase 1

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The role of heme oxygenase-1 in hematopoietic system and its microenvironment

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03803-z ◽

2021 ◽

Author(s):

Agata Szade ◽

Krzysztof Szade ◽

Mahdi Mahdi ◽

Alicja Józkowicz

Keyword(s):

Bone Marrow ◽

Heme Oxygenase ◽

Critical Role ◽

Heme Oxygenase 1 ◽

Bone Marrow Niche ◽

Cellular Mechanisms ◽

High Turnover ◽

Hematopoietic Stem ◽

Hematopoietic System

AbstractHematopoietic system transports all necessary nutrients to the whole organism and provides the immunological protection. Blood cells have high turnover, therefore, this system must be dynamically controlled and must have broad regeneration potential. In this review, we summarize how this complex system is regulated by the heme oxygenase-1 (HO-1)—an enzyme, which degrades heme to biliverdin, ferrous ion and carbon monoxide. First, we discuss how HO-1 influences hematopoietic stem cells (HSC) self-renewal, aging and differentiation. We also describe a critical role of HO-1 in endothelial cells and mesenchymal stromal cells that constitute the specialized bone marrow niche of HSC. We further discuss the molecular and cellular mechanisms by which HO-1 modulates innate and adaptive immune responses. Finally, we highlight how modulation of HO-1 activity regulates the mobilization of bone marrow hematopoietic cells to peripheral blood. We critically discuss the issue of metalloporphyrins, commonly used pharmacological modulators of HO-1 activity, and raise the issue of their important HO-1-independent activities.

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Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury

Biomedicines ◽

10.3390/biomedicines9030306 ◽

2021 ◽

Vol 9 (3) ◽

pp. 306

Author(s):

Maxime Rossi ◽

Kéziah Korpak ◽

Arnaud Doerfler ◽

Karim Zouaoui Boudjeltia

Keyword(s):

Reperfusion Injury ◽

Heme Oxygenase ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Macrophage Polarization ◽

Critical Role ◽

Kidney Injury ◽

Heme Oxygenase 1

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages.

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