Poly(adenosine diphosphate ribose) metabolism and regulation of myocardial cell growth by oxygen

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Abstract
Control of the rate of cardiac cell division by oxygen occurs most probably by altering the redox state of a control substance, e.g. NAD+⇌NADH. NAD+(and not NADH) forms poly(ADP-ribose), an inhibitor of DNA synthesis, in a reaction catalysed by poly(ADP-ribose) polymerase. Lower partial pressure of oxygen, which increases the rate of division, would shift NAD+→NADH, decrease poly(ADP-ribose) synthesis, and increase DNA synthesis. Chick-embryo heart cells grown in culture in 20% O2 (in which they divide more slowly than in 5% O2) did exhibit greater poly(ADP-ribose) polymerase activity (+83%, P2. Reaction product was identified as poly(ADP-ribose) by its insensitivity to deoxyribonuclease, ribonuclease, NAD glycohydrolase, Pronase, trypsin and micrococcal nuclease, and by its complete digestion with snake-venom phosphodiesterase to phosphoribosyl-AMP and AMP. Isolation of these digestion products by Dowex 1 (formate form) column chromatography and paper chromatography allowed calculation of average poly(ADP-ribose) chain length, which was 15–26% greater in 20% than in 5% O2. Thus in 20% O2 the increase in poly(ADP-ribose) formation results from chain elongation. Formation of new chains also occurs, probably to an even greater degree than chain elongation. Additionally, poly(ADP-ribose) polymerase has very different Km and Vmax. values and pH optima in 20% and 5% O2. These data suggest that poly(ADP-ribose) metabolism participates in the regulation of heart-cell division by O2, probably by several different mechanisms.