Hui-Zhong Zhou

Effect of anoxia/reperfusion on the reversible active/de-active transition of NADH-ubiquinone oxidoreductase (complex I) in rat heart.

The multi-subunit mammalian NADH-ubiquinone oxidoreductase (complex I) is part of the mitochondrial electron transport chain and physiologically serves to reduce ubiquinone with NADH as the electron donor. The three-dimensional structure of this enzyme complex remains to be elucidated and also little is known about the physiological regulation of complex I. The enzyme complex in vitro is known to exist as a mixture of active (A) and de-active (D) forms [Biochim. Biophys. Acta 1364 (1998) 169]. Studies are reported here examining the effect of anoxia and reperfusion on the A/D-equilibrium of complex I in rat hearts ex vivo. Complex I from the freshly isolated rat heart or after prolonged (1 h) normoxic perfusion exists in almost fully active form (87+/-2%). Either 30 min of nitrogen perfusion or global ischemia decreases the portion of active form of complex I to 40+/-2%. Upon re-oxygenation of cardiac tissue, complex I is converted back predominantly to the active form (80-85%). Abrupt alternation of anoxic and normoxic perfusion allows cycling between the two states of the enzyme. The possible role in the physiological regulation of complex I activity is discussed.

Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury.

The cardioprotective effectiveness of low-dose pyrroloquinoline quinone (PQQ, 3 mg/kg) was compared with metoprolol, a β1-selective adrenoceptor antagonist. Rats underwent 30 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Metoprolol and/or PQQ were given at the onset of reperfusion to mimic clinical treatment. Metoprolol and/or PQQ reduced infarct size and protected against ischemia-induced left ventricular dysfunction after 2 hours of reper-fusion. Combined therapy augmented left ventricular developed pressure at the end of reperfusion. Metoprolol or PQQ alone enhanced mitochondrial respiratory ratios in ischemic and nonischemic myocardium. Although the PQQ/metoprolol combination therapy increased respiratory ratio values, the effects were small when compared with PQQ alone. Only PQQ decreased lipid peroxidation. Metoprolol and/or PQQ given at the onset of reperfusion reduce infarct size and improve cardiac function. Combination therapy further reduces infarct size. PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage

Pyrroloquinoline Quinone (PQQ) Decreases Myocardial Infarct Size and Improves Cardiac Function in Rat Models of Ischemia and Ischemia/Reperfusion

SummaryAs pyrroloquinoline quinone (PQQ) is a redox cofactor in mammals, we asked if it is cardioprotective. Rats were subjected to 2 h of left anterior descending (LAD) coronary artery ligation without reperfusion (model 1, ischemia). In model 2 (ischemia/reperfusion), rats were subjected to 17 or 30 min of LAD occlusion and 2 h of reperfusion. PQQ (15–20 mg/kg) was given i.p., either 30 min before LAD occlusion (Pretreatment) or i.v. at the onset of reperfusion (Treatment). In model 1, PQQ reduced infarct size (10.0 ± 1.5 vs 19.1 ± 2.1%, P < 0.01). In model 2, either PQQ Pretreatment or Treatment also reduced infarct size (18.4 ± 2.3 and 25.6 ± 3.5% vs 38.1 ± 2.6%, P < 0.01). PQQ resulted in higher LV developed pressure and LV (+)dP/dt after 1–2 h of reperfusion (P < 0.05), and fewer ventricular fibrillation episodes. PQQ dose (5–20 mg/kg) was inversely related to infarct size. PQQ reduced myocardial tissue levels of malondialdehyde (MDA), an indicator of lipid peroxidation (316 ± 88 vs 99 ± 14 nmol/g, P < 0.01). PQQ given either as Pretreatment or as Treatment at the onset of reperfusion is highly effective in reducing infarct size and improving cardiac function in a dose-related manner in rat models of ischemia and ischemia/reperfusion. The optimal dose in this study, which exhibited neither renal nor hepatic toxicity, was 15 mg/kg, but lower doses may also be efficacious. We conclude that PQQ, which appears to act as a free radical scavenger in ischemic myocardium, is a highly effective cardioprotective agent.