Saxagliptin Prevents Increased Coronary Vascular Stiffness in Aortic-Banded Mini Swine
Saxagliptin Prevents Increased Coronary Vascular Stiffness in Aortic-Banded Mini Swine
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DOI：
10.1161/hypertensionaha.118.10993
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发表时间：
2018-08-01
期刊：
影响因子：
8.3
通讯作者：
Emter, Craig A.
中科院分区：
文献类型：
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作者：
Fleenor, Bradley S.;Ouyang, An;Emter, Craig A.
射血分数保留的心力衰竭（HF）患者外周导管动脉硬度增加。然而，尚不清楚这种现象是否延伸到冠状血管。保留射血分数的HF可能部分由冠状动脉炎症驱动，抑制DPP-4酶（二肽基肽酶4）可减少炎症和氧化应激。本研究的目的是确定沙格列汀DPP-4抑制剂对主动脉带状迷你猪冠状动脉僵硬的影响。我们假设沙格列汀可以通过抑制血管周围脂肪组织炎症来预防具有保留射血分数的HF心脏特征的平移猪模型冠状动脉僵硬增加。将尤卡坦迷你猪分为3组：对照组、主动脉带状非治疗HF组和沙格列汀主动脉带状非治疗HF组。对左旋冠状动脉和右冠状动脉进行离体力学测试，并测量晚期糖基化终产物NF-B（核因子b）和硝基酪氨酸水平。与对照组和沙格列汀治疗预防相比，HF动物冠状动脉弹性模量的增加与血管晚期糖基化终产物、NF-B和硝基酪氨酸水平的增加有关。用猪血管周围脂肪组织培养培养基处理健康小鼠主动脉，观察其对血管硬化的作用。HF和沙格列汀处理的HF动物的条件培养基增加了小鼠主动脉僵硬度；然而，只有HF组的血管周围脂肪组织显示晚期糖基化终产物和NF-B水平升高。总之，我们的数据显示，在猪模型中，沙格列汀可以防止冠状动脉血管僵硬增加，并与晚期糖基化终产物、NF-B和硝基酪氨酸水平的降低有关，这与保留射血分数的HF有潜在的相关性。
Increased peripheral conduit artery stiffness has been shown in patients with heart failure (HF) with preserved ejection fraction. However, it is unknown whether this phenomenon extends to the coronary vasculature. HF with preserved ejection fraction may be driven, in part, by coronary inflammation, and inhibition of the enzyme DPP-4 (dipeptidyl-peptidase 4) reduces inflammation and oxidative stress. The purpose of this study was to determine the effect of saxagliptina DPP-4 inhibitoron coronary stiffness in aortic-banded mini swine. We hypothesized saxagliptin would prevent increased coronary artery stiffness in a translational swine model with cardiac features of HF with preserved ejection fraction by inhibiting perivascular adipose tissue inflammation. Yucatan mini swine were divided into 3 groups: control, aortic-banded untreated HF, and aortic-banded saxagliptin-treated HF. Ex vivo mechanical testing was performed on the left circumflex and right coronary arteries, and advanced glycation end product, NF-B (nuclear factor-B), and nitrotyrosine levels were measured. An increase in the coronary elastic modulus of HF animals was associated with increased vascular advanced glycation end products, NF-B, and nitrotyrosine levels compared with control and prevented by saxagliptin treatment. Aortas from healthy mice were treated with media from swine perivascular adipose tissue culture to assess its role on vascular stiffening. Conditioned media from HF and saxagliptin-treated HF animals increased mouse aortic stiffness; however, only perivascular adipose tissue from the HF group showed increased advanced glycation end products and NF-B levels. In conclusion, our data show increased coronary conduit vascular stiffness was prevented by saxagliptin and associated with decreased advanced glycation end products, NF-B, and nitrotyrosine levels in a swine model with potential relevance to HF with preserved ejection fraction.