Wassenaar Jean W, Gaetani Roberto, Garcia Julian J, Braden Rebecca L, Luo Colin G, Huang Diane, DeMaria Anthony N, Omens Jeffrey H, Christman Karen L
Department of Bioengineering, University of California, San Diego; Sanford Consortium for Regenerative Medicine.
Department of Medicine, University of California, San Diego, La Jolla, California.
J Am Coll Cardiol. 2016 Mar 8;67(9):1074-1086. doi: 10.1016/j.jacc.2015.12.035.
There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models.
This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection.
Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways.
Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics.
These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.
对于更好的疗法以预防心肌梗死后心力衰竭的发生，需求日益增加。一种源自脱细胞猪心室心肌的可注射水凝胶已被证明，在小型和大型动物模型中均能阻止梗死后期左心室负性重构的进展以及心脏功能的下降。
本研究旨在阐明心肌基质注射治疗益处背后的组织水平机制。
在Sprague-Dawley大鼠缺血再灌注1周后，将心肌基质或生理盐水注射到梗死心肌中。在注射后5周通过磁共振成像和血流动力学测量评估心脏功能。在注射后3天和1周，对从梗死灶分离的RNA进行全转录组微阵列分析。定量聚合酶链反应和组织学定量证实关键基因的表达及其在改变通路中的激活。
转录组的主成分分析表明，从注射心肌基质的梗死灶收集的样本与注射生理盐水的对照样本不同且单独聚类。通路分析表明，这些差异是由于几个组织过程的变化所致，这些变化可能有助于改善心肌梗死后的心脏愈合。注射基质的梗死心肌表现出炎症反应改变、心肌细胞凋亡减少、梗死灶新生血管形成增强、心脏肥大和纤维化减轻、代谢酶表达改变、心脏转录因子表达增加以及祖细胞募集，同时整体心脏功能和血流动力学得到改善。
这些结果表明，心肌基质在心肌梗死后改变了几个关键通路从而创造了一个促再生环境，进一步证明了其作为心肌梗死后潜在治疗方法的前景。
