Chu Po-Yin, Joshi Mandar S, Horlock Duncan, Kiriazis Helen, Kaye David M
Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Front Pharmacol. 2019 Feb 19;10:117. doi: 10.3389/fphar.2019.00117. eCollection 2019.
Myocardial fibrosis is a key pathologic finding in the failing heart and is implicated as a cause of increased ventricular stiffness and susceptibility to ventricular arrhythmia. Neurohormonal mediators such as aldosterone and angiotensin II are known to cause fibrosis in experimental models, however, clinical evidence for the reversal of fibrosis with relevant antagonists is limited. Recent studies suggest that inflammatory mediators may contribute to fibrosis. In dilated cardiomyopathy the mechanism for myocardial fibrosis is unclear and its implications on systolic function are not known. We studied the effect of a highly selective antagonist of SDF-1/CXCR4 signaling, AMD3100, on the development of cardiac fibrosis and cardiac function in mice with dilated cardiomyopathy due to cardiac-specific transgenic overexpression of the stress-kinase, Mst1. AMD3100 significantly attenuated the progression of myocardial fibrosis and this was accompanied by significant improvements in diastolic and systolic performance as evaluated in isolated Langendorff perfused hearts. AMD3100 reduced BNP mRNA expression but did not alter the expression of Ca handling genes. CXCR4 antagonism also reduced the abundance of splenic CD4 T cells. This study demonstrates that CXCR4 pathway contributes to pathogenesis of cardiac fibrosis in dilated cardiomyopathy, and it represents a new potential therapeutic target in heart failure. The data also demonstrate that anti-fibrotic strategies can improve systolic performance.
心肌纤维化是心力衰竭的关键病理表现，被认为是心室僵硬度增加和易发生室性心律失常的原因。已知醛固酮和血管紧张素II等神经激素介质在实验模型中可导致纤维化，然而，使用相关拮抗剂逆转纤维化的临床证据有限。最近的研究表明，炎症介质可能促成纤维化。在扩张型心肌病中，心肌纤维化的机制尚不清楚，其对收缩功能的影响也未知。我们研究了一种高度选择性的SDF-1/CXCR4信号拮抗剂AMD3100对因心脏特异性转基因过度表达应激激酶Mst1而导致扩张型心肌病的小鼠心脏纤维化发展和心脏功能的影响。AMD3100显著减轻了心肌纤维化的进展，并且在离体Langendorff灌注心脏中评估时，这伴随着舒张和收缩功能的显著改善。AMD3100降低了BNP mRNA表达，但未改变钙处理基因的表达。CXCR4拮抗作用还减少了脾脏CD4 T细胞的数量。这项研究表明，CXCR4途径促成了扩张型心肌病中心脏纤维化的发病机制，并且它代表了心力衰竭中的一个新的潜在治疗靶点。数据还表明，抗纤维化策略可以改善收缩功能。
