Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, USA.
Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R763-8. doi: 10.1152/ajpregu.00220.2011. Epub 2011 Jun 29.
Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVC(max), P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVC(max), P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVC(max), P < 0.001) or combined with arginase inhibition (96 ± 3% CVC(max), P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVC(max), both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVC(max), P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVC(max,) P > 0.05) or combined with arginase inhibition (67 ± 4% CVC(max,) P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.
升高的低密度脂蛋白（LDL）与皮肤微血管功能障碍有关，部分原因是精氨酸酶活性增加，而这种活性在全身阿托伐他汀治疗后会降低。我们假设，升高的抗坏血酸敏感的氧化应激，部分是由上调的精氨酸酶诱导的无偶联的一氧化氮合酶（NOS）引起的，这导致了高脂血症（HC）人群的皮肤微血管功能障碍。在 9 名高胆固醇血症（HC）（LDL = 177 ± 6 mg/dl）男性和女性以及 9 名正常胆固醇血症（NC）（LDL = 95 ± 4 mg/dl）受试者的皮肤中放置了 4 个微透析纤维，在进行 3 个月的全身阿托伐他汀干预前和干预后，并在基线时进行了测量。这些部位被用作对照、NOS 抑制、L-抗坏血酸和精氨酸酶抑制+L-抗坏血酸。在所有部位达到稳定平台后，输注 20 mM ≪ngname≫以量化依赖于 NO 的血管舒张。将数据归一化为最大皮肤血管传导率（CVC）（硝普钠+43°C）。局部加热（42°C）诱导的 NO 依赖性血管舒张的平台在 HC 组（78 ± 4% CVC（max））与 NC 组（96 ± 2% CVC（max））相比降低（P < 0.01），NO 依赖性血管舒张也降低（HC 组：40 ± 4% CVC（max），P < 0.01）。单独的急性 L-抗坏血酸（91 ± 5% CVC（max），P < 0.001）或与精氨酸酶抑制联合使用（96 ± 3% CVC（max），P < 0.001）均可增加 HC 组的血管舒张平台，但不能增加 NC 组（抗坏血酸：96 ± 2% CVC（max）；联合治疗：93 ± 4% CVC（max），两者 P > 0.05）。阿托伐他汀干预后，HC 组的 NO 依赖性血管舒张增加（HC 组阿托伐他汀后：64 ± 4% CVC（max），P < 0.01），单独使用抗坏血酸或与精氨酸酶抑制联合使用均无进一步作用（58 ± 4% CVC（max），P > 0.05）或（67 ± 4% CVC（max），P > 0.05）。升高的抗坏血酸敏感的氧化剂有助于与高胆固醇血症相关的皮肤微血管功能障碍，阿托伐他汀治疗部分逆转了这种功能障碍。
