Wang Zhang-Feng, Wang Ning-Ping, Harmouche Suzanna, Philip Tiji, Pang Xue-Fen, Bai Feng, Zhao Zhi-Qing
Department of Otolaryngology, First Affiliated Hospital of Sun Yat-Sen University, Guang Zhou, P. R. China.
Cardiovascular Research Laboratory, Mercer University School of Medicine, Savannah, Georgia.
J Surg Res. 2017 May 1;211:178-190. doi: 10.1016/j.jss.2016.11.046. Epub 2016 Dec 5.
Postconditioning (Postcon) is known to reduce infarct size. This study tested the hypothesis that Postcon attenuates the perivascular and interstitial fibrosis after myocardial infarction through modulating angiotensin II-activated fibrotic cascade.
Male Sprague-Dawley rats were subjected to 45-min coronary occlusion followed by 1 and 6 wk of reperfusion. Postcon was applied at the onset of reperfusion with four cycles of 10/10-s reperfusion-ischemia at the onset of reperfusion. Preconditioning (Precon) with two cycles of 5/5-min ischemia-reperfusion was applied before coronary occlusion.
Postcon reduced angiotensin-converting enzyme protein and expression in the perivascular area and intermyocardium, coincident with the less-expressed angiotensin II receptor, type 1, enhanced angiotensin II receptor, type 2, and angiotensin converting enzyme 2. Postcon lowered the monocyte chemoattractant protein-1 and inhibited the populations of interstitial macrophages (60 ± 12 versus 84 ± 9.5 number per high-powered field [HPF] in control, P < 0.05). Along with these modulations, Postcon also downregulated transforming growth factor β1 protein and inhibited proliferation of α-smooth muscle actin expressing myofibroblasts (41 ± 11 versus 79 ± 8.2 number per HPF in control, P < 0.05), consistent with downregulated phospho-Smad2 and phospho-Smad3. Furthermore, the synthesis of collagen I and III was attenuated, and the perivascular-interstitial fibrosis was inhibited by Postcon as demonstrated by reduced perivascular fibrosis ratio (0.6 ± 0.6 versus 1.6 ± 0.5 per HPF in control, P < 0.05) and smaller collagen-rich area (16 ± 4.7 versus 34 ± 9.2% per HPF in control, P < 0.05). Precon conferred a comparable level of protection as Postcon did in all parameters measured, suggesting protection trigged by this endogenous stimulation can be achieved when it was applied either before ischemia or after reperfusion.
These results suggest that Postcon could be selected as an adjunctive intervention with other existing therapeutic drugs to treat the fibrosis-derived heart failure patients after myocardial infarction.
已知后适应（Postcon）可减小梗死面积。本研究检验了以下假设：后适应通过调节血管紧张素II激活的纤维化级联反应，减轻心肌梗死后的血管周围和间质纤维化。
将雄性Sprague-Dawley大鼠冠状动脉闭塞45分钟，随后再灌注1周和6周。在再灌注开始时进行后适应，采用四个周期的10/10秒再灌注-缺血，在再灌注开始时进行。在冠状动脉闭塞前采用两个周期的5/5分钟缺血-再灌注进行预处理（Precon）。
后适应降低了血管紧张素转换酶在血管周围区域和心肌内的蛋白及表达，同时1型血管紧张素II受体表达减少，2型血管紧张素II受体和血管紧张素转换酶2表达增强。后适应降低了单核细胞趋化蛋白-1水平，并抑制了间质巨噬细胞数量（对照组每高倍视野[HPF]为84±9.5个，后适应组为60±12个，P<0.05）。伴随着这些调节，后适应还下调了转化生长因子β1蛋白，并抑制了表达α-平滑肌肌动蛋白的肌成纤维细胞的增殖（对照组每HPF为79±8.2个，后适应组为41±11个，P<0.05），这与磷酸化Smad2和磷酸化Smad3的下调一致。此外，I型和III型胶原的合成减弱，后适应抑制了血管周围-间质纤维化，表现为血管周围纤维化比率降低（对照组每HPF为1.6±0.5，后适应组为0.6±0.6，P<0.05）和富含胶原区域减小（对照组每HPF为34±9.2%，后适应组为16±4.7%，P<0.05）。预处理在所有测量参数中提供了与后适应相当的保护水平，表明这种内源性刺激引发的保护作用，无论是在缺血前还是再灌注后应用均可实现。
这些结果表明，后适应可作为一种辅助干预措施，与其他现有治疗药物联合使用，用于治疗心肌梗死后纤维化所致心力衰竭患者。
