Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate

被引:45
作者
Biolo, Andreia [2 ,3 ]
Greferath, Ruth [1 ,4 ]
Siwik, Deborah A. [2 ,3 ]
Qin, Fuzhong [2 ,3 ]
Valsky, Eugene [2 ,3 ]
Fylaktakidou, Konstantina C. [1 ]
Pothukanuri, Srinivasu [1 ]
Duarte, Carolina D. [1 ]
Schwarz, Richard P.
Lehn, Jean-Marie [1 ]
Nicolau, Claude [1 ,4 ,5 ]
Colucci, Wilson S. [2 ,3 ]
机构
[1] Univ Strasbourg, Inst Sci & Ingn Supramol, F-67000 Strasbourg, France
[2] Boston Univ, Med Ctr, Dept Med, Cardiovasc Sect, Boston, MA 02215 USA
[3] Boston Univ, Sch Med, Myocardial Biol Unit, Boston, MA 02215 USA
[4] NormOxys Inc, Medford, MA 02155 USA
[5] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
hypoxia; oxygen delivery; OXYGEN; ERYTHROCYTES; BINDING; CELLS;
D O I
10.1073/pnas.0812381106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1 alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.
引用
收藏
页码:1926 / 1929
页数:4
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