Moore G, Liao S, Curci J A, Starcher B C, Martin R L, Hendricks R T, Chen J J, Thompson R W
Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
J Vasc Surg. 1999 Mar;29(3):522-32. doi: 10.1016/s0741-5214(99)70281-8.
Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs.
Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy.
AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation.
Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs.
腹主动脉瘤（AAA）与慢性炎症、中膜弹性蛋白破坏以及弹性蛋白酶解基质金属蛋白酶（MMP）的局部产生增加有关。本研究的目的是探讨基于异羟肟酸的MMP拮抗剂（RS 132908）治疗如何影响实验性AAA的发展。
雄性Wistar大鼠接受腹主动脉腔内灌注50单位猪胰弹性蛋白酶，随后用RS 132908（100mg/kg/天皮下注射；n = 8）或仅用载体（n = 6）治疗14天。在弹性蛋白酶灌注前和处死时以毫米为单位测量主动脉外径（AD），AAA定义为AD增加（ΔAD）至少100%。用去甲鸟氨酸和羟脯氨酸测定法测量主动脉壁弹性蛋白和胶原蛋白浓度，并用光学显微镜检查固定的主动脉组织。
所有接受载体治疗的大鼠均发生AAA，平均AD（±SE）从灌注前的1.60±0.03mm增加到第14天的5.98±1.02mm（ΔAD = 276.4±67.7%）。MMP抑制后，8只动物中只有5只（62.5%）发生AAA，平均AD从1.56±0.05mm增加到3.59±0.34mm（ΔAD = 128.1±18.7%；与载体相比，P <.05）。RS 132908对主动脉扩张的总体抑制率为53.6±6.8%。在接受载体治疗的大鼠中，主动脉壁去甲鸟氨酸下降了85.4%（从1210.6±87.8pmol/样本降至176.7±33.4pmol/样本；P <.05），但在接受RS 312908治疗的动物中仅下降了65.6%（416.2±120.5pmol/样本）。相比之下，羟脯氨酸不受弹性蛋白酶灌注或药物治疗的显著影响。显微镜检查显示，MMP抑制后细胞周围弹性蛋白得以保留，纤维胶原性壁增厚程度更大，炎症程度无明显差异。
在弹性蛋白酶诱导的AAA啮齿动物模型中，全身MMP抑制可抑制动脉瘤扩张。与其对各种MMP的直接抑制作用一致，RS 132908促进主动脉弹性蛋白的保留，并似乎增强主动脉壁内的促纤维化反应。因此，基于异羟肟酸的MMP拮抗剂可能有助于开发抑制AAA的药理学方法。
