Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling
Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling
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DOI：
10.1161/hypertensionaha.120.16445
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发表时间：
2021-06-01
期刊：
影响因子：
8.3
通讯作者：
Saito, Yoshihiko
中科院分区：
文献类型：
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作者：
Nakagawa, Hitoshi;Kumazawa, Takuya;Saito, Yoshihiko
NEP （Neprilysin）可降解利钠肽，其抑制作用是临床公认的心力衰竭治疗靶点。NEP在包括心脏在内的各种器官中广泛表达。然而，局部心脏NEP的病理生理意义尚不完全清楚。为了研究NEP在心脏中的局部功能，我们制造了过表达NEP的转基因小鼠，特别是在心肌细胞中（CM-NEP Tg）。在基线时，CM-NEP Tg小鼠与野生型（WT）小鼠相比，血浆ANP（心房利钠肽）、血浆cGMP和心脏组织cGMP水平显著降低。CM-NEP Tg小鼠的血压、心脏重量和心肌细胞直径均高于WT小鼠。两组间质纤维化和射血分数无显著差异。与假手术相比，横断主动脉收缩术（TAC）术后3周显著增加WT和CM-NEP Tg小鼠左心室重量；然而，CM-NEP Tg小鼠对TAC的心脏肥厚反应高于WT小鼠。TAC CM-NEP Tg小鼠可诱导心肌间质纤维化，而TAC WT小鼠则没有。超声心动图显示，TAC CM-NEP Tg，而不是TAC WT，小鼠出现TAC继发心功能障碍。此外，在TAC后CM-NEP Tg小鼠中，给药人ANP以提高与WT小鼠相当的血浆ANP水平，既不能改善加重的心肌肥大和纤维化，也不能恢复受损的心功能。综上所述，心肌细胞中NEP的过度表达促进了心脏内利钠肽的降解，并导致心肌肥大和纤维化对压力过载的过度反应。
NEP (Neprilysin) degrades natriuretic peptides, and its inhibition is a clinically accepted target for heart failure treatment. NEP is widely expressed in various organs, including the heart. However, the pathophysiological significance of local cardiac NEP is not fully understood. To study the local function of NEP in the heart, we generated transgenic mice overexpressing NEP, specifically in cardiomyocytes (CM-NEP Tg). At baseline, CM-NEP Tg mice showed significantly lower levels of plasma ANP (atrial natriuretic peptide), plasma cGMP, and cardiac tissue cGMP versus wild-type (WT) mice. Blood pressure, heart weight, and cardiomyocyte diameter were greater in CM-NEP Tg than WT mice. There were no significant differences in interstitial fibrosis or ejection fraction. Transverse aortic constriction (TAC) surgery significantly increased left ventricular weight in WT and CM-NEP Tg mice 3 weeks post-op versus sham surgery; however, the cardiac hypertrophic response to TAC was higher in CM-NEP Tg than WT mice. Cardiac interstitial fibrosis was induced in TAC CM-NEP Tg mice, whereas TAC WT mice had none. TAC CM-NEP Tg, but not TAC WT, mice developed cardiac dysfunction secondary to TAC with echocardiography. Furthermore, administration of human ANP to raise plasma ANP levels comparable to those in WT mice neither improved the exacerbated cardiac hypertrophy and fibrosis nor recovered impaired cardiac function in CM-NEP Tg mice after TAC. In conclusion, overexpression of NEP in cardiomyocytes promoted degradation of natriuretic peptides in the heart and led to an exaggerated response of hypertrophy and fibrosis to pressure overload.