Hypoxia-induced cell membrane

In studies in vitro, caspases are involved in hypoxic [62,64] injury to RTE cells. Antimycin A-induced chemical hypoxia [64] or growth under hypoxic conditions results in increased caspase activity and pancaspase inhibition prevents hypoxia-induced DNA fragmentation and cell death in RTE cells. Partial ATP depletion of MDCK cells by antimycin A was also shown to result in apoptosis with marked increase in activation of caspase-8 and inhibition of caspases provided marked protection against antimycin A-induced cell death [65]. Exposure of freshly isolated RTE to hypoxia resulted in caspase activation and cell membrane damage [66]. In a related study, activation of caspase-3 during hypoxia or ATP depletion was shown to be accompanied by bax translocation and cytochrome c release [67]. As in ischemia, cisplatin activates the caspase cascade as well. Cisplatin induces selective and differential activation of caspases including executioner caspase-3... 

We have hypothesized and then experimentally demonstrated that antibody-directed liposomes specific for an intracellular cytoskeletal antigen can have two important medical applications prevention of hypoxia-induced release of intracellular contents and subsequent cell death by sealing (plugging) membrane lesions with such ILs, and use of ILs for the targeted intracellular delivery of pharmacologically important substances, such as drugs or genetic constructs. 

Fig. 4.22. Hypoxia-mediated metabolic adaptation for energy preservation. Activation of genes for glucose transporter-1 (GLUT-1 = 1) and glycolytic enzymes yields an increased glycolytic rate. H -ions produced are preferentially exported via a Na /H -antiporter (NHE-1 = 3) and a lactate /H -symporter (monocarboxylate transporter MCT-1 = 2) leading to a drop in extracellular pH (pH.). Low extracellular pH activates the membrane-bound ectoenzyme carbonic anhydrase IX (CA IX = 4). Key mechanism regulating intracellular pH in tumor cells when protons are produced is also shown (Na -depen-dent HCOs" /CL -exchanger = 5). HIF-Ia = hypoxia-inducible factor la, PHDs = prolyl hydroxylases, FIH = asparagyl hydroxylase, lac" = lactic acid...

It is now widely accepted that the rise in type I cell [Ca ] induced by hypoxia is due to cell membrane depolarization and the resulting Ca influx via voltage-gated... 

That glomus cells exhibit membrane and cytoplasmic changes in response to hypoxia is very well documented (see Refs. 52-54), but the only way to demonstrate that hypoxia-induced glomus cell excitation initiates the full chemoreceptor process is by recording sensory discharges from the adjacent nerve fibers. 

Figure 3 Effects of various stimuli and mitochondrial inhibitors on the resting membrane potential of quiescent chromaffin cells. A typical example of hypoxia-induced membrane depolarization is shown in (a), using nystatin perforated-patch whole-cell recording. In (b), bicuculline (100 pM), a reversible inhibitor of small-conductance Ca +-dependent K+ channels (SK), also caused membrane depolarization similar to hypoxia. The mitochondrial inhibitors 2,4-drnitrophenol (DNP) and cyanide (CN) did not mimic the h poxia-mduced membrane depolarization seen in (c) and (d), respectively in fact, in (d), CN caused membrane h3q)erpolarization, though in most cases no change in membrane potential was observed. Both DNP and CN were usually without effect even after perfusing the drug for >10 min. In (e), the hyperpolarizing effect of CN was reversed in the presence of 200 pM glibenclamide, a blocker of Katp channels.

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