Anfossi Giovanni, Russo Isabella, Massucco Paola, Mattiello Luigi, Trovati Mariella
Diabetes Unit, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, I-10043 Orbassano, Turin, Italy.
Thromb Res. 2003 Apr 15;110(1):39-46. doi: 10.1016/s0049-3848(03)00284-6.
We investigated whether the platelets from obese subjects are sensitive as those from controls to the antiaggregating effects of N-acetyl-L-cysteine (NAC)-an antioxidant thiol that increases availability of endogenous nitric oxide (NO)-and of superoxide dismutase (SOD) and amifostine which act as scavengers of superoxide anion.
In platelets from obese subjects (n=20, body mass index [BMI]=34.2+/-1.9 kg/m(2), homeostasis model assessment [HOMA] index=5.5+/-1.1) and controls (n=20, BMI=21.4+/-0.6 kg/m(2), HOMA index=1.4+/-0.2), we investigated the effects of NAC on aggregation and on 3',5'-cyclic guanosine monophosphate (cGMP) synthesis and the interplay between NAC and the organic nitrates glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). Similar experiments were carried out with SOD and amifostine.
We found that a 3-min platelet exposure to NAC decreased aggregation and increased cGMP in controls, but not in obese subjects. Only more prolonged incubations exerted a small effect also in obese subjects. GTN and SNP increased platelet cGMP in both groups, but their effect was much lower in obese subjects. NAC (3 mmol/l), SOD (150 U/ml), and amifostine (50 micromol/l) enhanced the increase of cGMP elicited by NO donors, but again, the effect was much lower in obese subjects.
Since antioxidants do not restore the effects of NO in platelets from obese subjects, we hypothesize that oxidative stress is not the unique cause of platelet resistance to NO in obesity and suggest that a resistance to the NO action at the guanylate cyclase level could play a role in this phenomenon, potentially involved in the increased atherothrombotic risk linked to obesity.
我们研究了肥胖受试者的血小板是否与对照组的血小板一样，对N - 乙酰 - L - 半胱氨酸（NAC）——一种可增加内源性一氧化氮（NO）可用性的抗氧化硫醇——以及作为超氧阴离子清除剂的超氧化物歧化酶（SOD）和氨磷汀的抗聚集作用敏感。
在肥胖受试者（n = 20，体重指数[BMI]=34.2±1.9 kg/m²，稳态模型评估[HOMA]指数=5.5±1.1）和对照组（n = 20，BMI = 21.4±0.6 kg/m²，HOMA指数=1.4±0.2）的血小板中，我们研究了NAC对聚集以及对3',5'-环鸟苷单磷酸（cGMP）合成的影响，以及NAC与有机硝酸盐硝酸甘油（GTN）和硝普钠（SNP）之间的相互作用。用SOD和氨磷汀进行了类似实验。
我们发现，血小板暴露于NAC 3分钟可降低对照组血小板的聚集并增加cGMP，但在肥胖受试者中则不然。只有更长时间的孵育对肥胖受试者也有微小作用。GTN和SNP在两组中均增加血小板cGMP，但在肥胖受试者中的作用要低得多。NAC（3 mmol/l）、SOD（150 U/ml）和氨磷汀（50 μmol/l）增强了NO供体引起的cGMP增加，但同样，在肥胖受试者中的作用要低得多。
由于抗氧化剂不能恢复肥胖受试者血小板中NO的作用，我们推测氧化应激不是肥胖中血小板对NO抵抗的唯一原因，并表明在鸟苷酸环化酶水平对NO作用的抵抗可能在这一现象中起作用，这可能与肥胖相关的动脉粥样硬化血栓形成风险增加有关。
