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BACKGROUND: Prosurvival signaling kinases inhibit glycogen synthase kinase-3β (GSK-3β) activity and stimulate apoptotic protein p53 degradation. Helium produces cardioprotection by activating prosurvival kinases, but whether GSK and p53 inhibition mediate this process is unknown. We tested the hypothesis that inhibition of GSK or p53 lowers the threshold of helium cardioprotection via a mitochondrial permeability transition pore (mPTP)-dependent mechanism.

METHODS: Rabbits (n = 85) instrumented for hemodynamic measurement and subjected to a 30 min left anterior descending coronary artery (LAD) occlusion and 3 h reperfusion received 0.9% saline (control), or 1, 3, or 5 cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture (fraction of inspired oxygen concentration = 0.30) before LAD occlusion. Other rabbits received the GSK inhibitor SB 216763 (SB21; 0.2 or 0.6 mg/kg), the p53 inhibitor pifithrin- (PIF; 1.5 or 3.0 mg/kg), or SB21 (0.2 mg/kg) or PIF (1.5 mg/kg) plus helium (1 cycle) before LAD occlusion in the presence or absence of the mPTP opener atractyloside (5 mg/kg).

RESULTS: Helium reduced (P < 0.05) myocardial infarct size (35 ± 6 [n = 7], 25 ± 4 [n = 7], and 20 ± 3% [n = 6] of area at risk, 1, 3, and 5 cycles, respectively) compared with control (44 ± 6% [n = 7]). SB21 (0.6 [n = 7] but not 0.2 mg/kg [n = 6]) and PIF (3.0 [n = 6] but not 1.5 mg/kg [n = 7]) also reduced necrosis. SB21 (0.2 mg/kg) or 1.5 mg/kg PIF (1.5 mg/kg) plus helium (1 cycle; n = 6 per group) decreased infarct size to an equivalent degree as three cycles of helium alone, and this cardioprotection was blocked by atractyloside (n = 7 per group).

CONCLUSIONS: Inhibition of GSK or p53 lowers the threshold of helium-induced preconditioning via a mPTP-dependent mechanism in vivo.

The Elegant Universe Superstrings, Hidden Dimensions, and the Quest for the Ultimate Theory
Written by Brian Greene

"[Greene] develops one fresh new insight after another...In the great tradition of physicists writing for the masses, The Elegant Universe sets a standard that will be hard to beat." --George Johnson, The New York Times Book Review

In a rare blend of scientific insight and writing as elegant as the theories it explains, Brian Greene, one of the world's leading string theorists, peels away the layers of mystery surrounding string theory to reveal a universe that consists of 11 dimensions where the fabric of space tears and repairs itself, and all matter-from the smallest quarks to the most gargantuan supernovas-is generated by the vibrations of microscopically tiny loops of energy.

Green uses everything from an amusement park ride to ants on a garden hose to illustrate the beautiful yet bizarre realities that modern physics is unveiling.    Dazzling in its brilliance, unprecedented in its ability to both illuminate and entertain, The Elegant Universe is a tour de force of science writing-a delightful, lucid voyage through modern physics that brings us closer than ever to understanding how the universe works.


From the Trade Paperback edition.