Hypoxia-Mediated Induction of Heme Oxygenase Type I and Carbon Monoxide Release from Astrocytes Protects Nearby Cerebral Neurons from Hypoxia-Mediated Apoptosis

Abstract

To study a putative paracellular protective mechanism of astrocytes for neurons, immunohistochemical analysis was performed in ischemic rat brain, which colocalized with the expression of heme oxygase-1 (HO- 1) in astroglias surrounding dying TUNEL-positive neurons. As an in vitro paradigm for ischemia, cultured astrocytes were exposed to normobaric hypoxia (pO(2) asymptotically equal to 10 torr), which triggered marked increase in the expression of a 33 kDa stress protein, identified as HO-1. Induction of HO-1 message was observed within 4 h of hypoxia and peaked at 12 h, accompanied by an accelerated transcription of HO-1 message. Consistent with the induction of HO-1, a platelet bioassay revealed production of carbon monoxide by reoxygenated astrocytes. The presence of CO in the medium decelerated the hypoxia-mediated apoptotic type of cell death in cultured cerebral neurons via lowering the activity of caspase-3, a key enzyme regulating apoptotic cell death. This protection against apoptosis was likely mediated by CO-mediated increases in intracellular cGMP, because exposure of hypoxic neurons to CO increased intracellular cGMP levels, and addition of cGMP analogue to hypoxic neuronal cultures suppressed caspase-3 activity and promoted neuronal survival. These data describe a potentially important paracellular pathway through which astrocytes may rescue nearby neurons from ischemic death.

Heme Oxygenase-1 as a Therapeutic Target in Neurodegenerative Diseases and Brain Infections

“…Thus, systemically administered CO to the brain, elicits vasodilator and cytoprotective effects in the cerebral circulation, has no long-term adverse effects, and protects the neonatal brain from cerebral vascular injury caused by epileptic seizures [41]. In cultured cerebral neurons CO decelerated hypoxiamediated apoptosis by lowering the activity of caspase-3 in a cGMP dependent manner [42]. Regarding inflammation, CO blocked TNF--and glutamate-induced reactive oxygen species accumulation and apoptosis in newborn pig cerebral microvascular endothelial cells [43,44].…”

Structural characterization of human heme oxygenase-1 in complex with azole-based inhibitors

“…The reaction catalyzed by HO is also the main source of CO in mammals, with $85% of the CO produced under normal physiological conditions being derived from heme. There has been increasing evidence of the cellular regulatory actions of CO including anti-inflammatory, antiapoptotic, antiproliferative, and vasodilatory effects [7][8][9][10]. Many of the effects of CO involve the increased synthesis of cyclic guanosine monophosphate (cGMP) by way of its activation of soluble guanylate cyclase (sGC) [11,12], activation of mitogen-activated protein kinase (MAPK) signaling pathways [13][14][15][16], and stimulation of calciumdependent potassium channels [17].…”

Cellular Prion Protein (PrPc) and Hypoxia: True to Each Other in Good Times and in Bad, in Sickness, and in Health

“…In addition, astrocytes are also efficient in decreasing ATP consumption when oxygen- and glucose-deprived (Yager et al, 1994). All these traits of astrocytic adaptation to low oxygen tensions presumably contribute to their role in safeguarding neurons from detrimental effects of anoxia and hypoxia (Vibulsreth et al, 1987; Imuta et al, 2007). Previous studies have demonstrated that after ischemic insult neurons fail to survive if neighboring astrocytes are not viable (Takano et al, 2009).…”