Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease

Abstract

Increases in cell death by programmed (ie., apoptosis, autophagy) or non-programmed mechanisms (ie., necrosis) occur during tissue injury, and may contribute to the etiology of several pulmonary or vascular disease states. The low molecular weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXα, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-κB, phosphatydylinositol-3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.Must not all things at the last be swallowed up in death? -Plato

Interleukin-34 Selectively Enhances the Neuroprotective Effects of Microglia to Attenuate Oligomeric Amyloid-β Neurotoxicity

“…30 These endproducts provide cellular and tissue protection through anti-inflammatory, anti-apoptotic, or antioxidative effects. 31 Because the neuroprotective effect of IL-34 was abolished by treatment with the HO-1 inhibitor SnMP, up-regulation of HO-1 in microglia by treatment with IL-34 may lead to neuroprotection against oA␤ toxicity through suppression of ROS. Moreover, less induction of neurotoxic molecules such as tumor necrosis factor-␣, NO, and glutamate in microglia may also contribute to neuroprotection by IL-34.…”

CXCR3-B Can Mediate Growth-inhibitory Signals in Human Renal Cancer Cells by Down-regulating the Expression of Heme Oxygenase-1

“…An increased level of ROS may promote significant damage to cell structure and functions (34). HO-1, a member of the heat shock protein family, plays a key role as a sensor and regulator of cellular oxidative stresses (35,36). HO-1 is induced in tissues during these stress conditions, and it promotes cytoprotection.…”

Mitochondrial quality-control dysregulation in conditional HO-1–/– mice

“…During oxidative stress, HO-1 eliminates cellular free heme (1), a powerful oxidant (2,3), and produces the physiological gas carbon monoxide (CO) (4), which has potent antiinflammatory and antiapoptotic effects and stimulates mitochondrial biogenesis (5,6). Moreover, administration of low-level CO gas or CO-releasing molecules mitigates many pathological injuries that affect energy metabolism in cells and tissues of experimental animals (7,8). Hmox1-deficient heart cells accumulate lethal molecular oxidant damage, and embryonic Hmox1 deletion in mice has a high prenatal mortality, with survivors showing growth retardation, iron overload, organ fibrosis, and inflammatory tissue damage (9).…”