Send letter to journal:
Re: HIF-1 and cellular fate

Dear Editor,

The authors of this paper observe that, "The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic....During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation".[1]

In myocytes the likelihood of devloping apoptosis appears to be dependent upon interstitial pH increasing as the pH falls to abnormally low levels[2] as it does when an energy deficit develops in cells.

In an earlier communication to Heart[3] it was asked, "Might it be that apoptosis, an ATP-dependent process, is an altruistic sacrifice intended to protect adjacent cells from the harmful effects of the inflammatory response induced by free radical release and cellular necrosis should it occur? [The absence of an inflammatory response in apoptosis is a striking feature distinguishing it from necrosis]. Might apoptosis even be a physiological stimulus for myocyte renewal?"

A corollary of this myocyte buddy hypothesis is that apoptotic cells might protect contiguous cells under reductive/oxidative stress by providing them with a supplementary supply of nutrients in times of stress independently of an overextended blood supply. Necrosis might only occur, and an inflammatory response be initiated, when this hypothetical supplementary supply of nutrient fails to meet the metabolic needs of stressed cells. [Anaerobic glycolysis is the dominant means of ATP resynthesis in healing wounds and malignant tumours but hardly ever to the total exclusion of oxygen. This implies that the dependence upon nutrient relative to oxygen delivery is abnormally increased in these circumstances].

What then determines the ultimate fate of cells? The studies cited above suggest that apoptosis and/or necrosis might only occur when the interstitial pH has fallen below 6.86 or even 6.80. In which case cells exposed to an abnormally low pH higher than that, possibly one between 7.32 and 6.90, might be subjected to increasing cellular disorder the effects of which could be an added risk of genetic damage and/or mutation. This could be an evolutionary advantage in unicellular organisms and one that might even be the product of quantum tunnelling.[4]

Cellular proliferation is induced under similar metabolic circumstances in an healing wound but must be accompanied by an abnormal elevation in pH because of the reductuive biosynthesis in progress. Angiogenesis, which also appear to be induced by the hypoxia inducible factor 1 [5], is presumably a prerequisite for the delivery of adequate nutrient to sustain the anaerobic glycolysis needed in an healing wound and indeed tumour growth. This requires an abnormally good supply of blood for much more nutrient must be delivered to generate 1 mol ATP by anaerobic glycolysis than by oxidative phosporylation. A return to a nornal tissue pH (7.40) can be expected to occur in an healed wound but might not occur in a growing tumour. Rapidly growing tumoursmight, however, be especially susceptible to a precipitous decline in pH induced by an nadequate supply of nutrient and hence to the cellular necrosis commonly seen in the center of a rapidly growing tumour.

The "intricate balance [that] exists between factors that induce or counteract apoptosis, or even stimulate proliferation"[1] and possibly even invasion and metastatic spread might be defined and even determined by the ambient pH. This appears not only to be an index of but might even be a determinant of[6] the metabolic environment present. The activity of HIF-1 may even be determined by the ambnient pH which falls precipitously in stagnant hypoxia unless preceded by cardiac arrest.[7]

References

1. A E Greijer and E van der Wall The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced Apoptosis. J Clin Pathol 2004; 57: 1009-1014.

2. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V, Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.

3. Richard G Fiddian-Green. A myocyte buddy system in stressed myocardium? http://www.heartjnl.com/cgi/eletters/90/4/425#393, 2 Aug 2004

4. Jim Al Khalili. Quantum: A Guide for the Perplexed.

5. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996 Sep;16(9):4604-13.

6. Cain SM. pH effects on lactate and excess lactate in relation to O2 deficit in hypoxic dogs. J Appl Physiol. 1977 Jan;42(1):44-9.

7. Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED, Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine. J Appl Physiol. 1984 Apr;56(4):1065-9.