Mechanisms that limit regression of myocardial fibrosis following removal of left ventricular pressure overload.
Mechanisms that limit regression of myocardial fibrosis following removal of left ventricular pressure overload.
复制标题
消除左心室压力超负荷后限制心肌纤维化消退的机制。
DOI：
10.1152/ajpheart.00148.2022
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Bradshaw,AmyD
中科院分区：
文献类型：
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作者：
Neff,LilyS;Zhang,Yuhua;VanLaer,AnO;Baicu,CatalinF;Karavan,Mark;Zile,MichaelR;Bradshaw,AmyD
左心室压力超负荷（LVPO）可由主动脉瓣狭窄和全身性高血压等既往疾病引起，其特征是心肌细胞外基质（ECM）积聚。来自患者和动物模型的证据支持 PO 缓解后 ECM 有限减少，然而，控制 ECM 消退程度和时间的机制尚不清楚。小鼠横向主动脉缩窄 (TAC) 4 周诱导的 LVPO 通过去除束带 (unTAC) 得到缓解。评估心肌细胞横截面积、胶原体积分数 (CVF)、心肌硬度和胶原降解：对照、2 周 TAC、4 周 TAC、4 周 TAC + 2 周 unTAC、4 周 TAC + 4 周 unTAC 和 4 周 TAC + 6 周 unTAC。与 4 周 TAC 相比，2 周 unTAC 导致胶原杂交肽 (CHP) 的反应性增加（代表胶原蛋白降解的开始）、胶原酶和明胶酶水平增加、胶原交联酶水平降低，但 CVF 没有变化。与 2 周 unTAC 相比，4 周 unTAC 表现出 CVF 降低，但并未下降至对照值。在 4 周和 6 周 unTAC 时，与 2 周 unTAC 相比，CHP 反应性和 ECM 降解介质降低，而金属蛋白酶组织抑制剂 (TIMP)-1 水平增加。去除 LVPO 后，ECM 稳态以时间依赖性方式发生变化，其特点是胶原蛋白降解早期增加，随后该过程逐渐减弱。预计随着时间的推移，缓和的 ECM 降解将有助于发现仅血流动力学超负荷正常化并不能完全逆转心肌纤维化。新的和值得注意的在这项研究中，小鼠模型在压力超负荷减轻后表现出持续的间质纤维化和心肌僵硬。
Left ventricular pressure overload (LVPO) can develop from antecedent diseases such as aortic valve stenosis and systemic hypertension and is characterized by accumulation of myocardial extracellular matrix (ECM). Evidence from patient and animal models supports limited reductions in ECM following alleviation of PO, however, mechanisms that control the extent and timing of ECM regression are undefined. LVPO, induced by 4 wk of transverse aortic constriction (TAC) in mice, was alleviated by removal of the band (unTAC). Cardiomyocyte cross-sectional area, collagen volume fraction (CVF), myocardial stiffness, and collagen degradation were assessed for: control, 2-wk TAC, 4-wk TAC, 4-wk TAC + 2-wk unTAC, 4-wk TAC + 4-wk unTAC, and 4-wk TAC + 6-wk unTAC. When compared with 4-wk TAC, 2-wk unTAC resulted in increased reactivity of collagen hybridizing peptide (CHP) (representing initiation of collagen degradation), increased levels of collagenases and gelatinases, decreased levels of collagen cross-linking enzymes, but no change in CVF. When compared with 2-wk unTAC, 4-wk unTAC demonstrated decreased CVF, which did not decline to control values. At 4-wk and 6-wk unTAC, CHP reactivity and mediators of ECM degradation were reduced versus 2-wk unTAC, whereas levels of tissue inhibitor of metalloproteinase (TIMP)-1 increased. ECM homeostasis changed in a time-dependent manner after removal of LVPO and is characterized by early increases in collagen degradation, followed by a later dampening of this process. Tempered ECM degradation with time is predicted to contribute to the finding that normalization of hemodynamic overload alone does not completely regress myocardial fibrosis.NEW & NOTEWORTHYIn this study, a murine model demonstrated persistent interstitial fibrosis and myocardial stiffness following alleviation of pressure overload.