血管平滑肌细胞KLF4对高血压小鼠模型心脏重塑的调控作用

The role of KLF4 in vascular smooth muscle cells on cardiac remodeling in mice with hypertension

目的 探讨血管平滑肌细胞Krüppel样因子4(Krüppel-like factor 4,KLF4)对高血压小鼠心脏重塑的调控作用。方法 采用皮下埋植缓释泵灌注血管紧张素II(angiotensin II,Ang II)28 d建立小鼠高血压模型,剂量1 500 ng/(kg·min)。构建他莫昔芬诱导的血管平滑肌细胞Klf4基因特异敲除(Klf4-SMKO)小鼠,9~10周龄雄性Klf4-SMKO和Klf4-flox野生型小鼠各13只,分别随机分为2组,共4组:野生对照组(Klf4-flox+生理盐水灌注,6只),Klf4敲除对照组(Klf4-SMKO+生理盐水,6只),野生高血压模型组(Klf4-flox+Ang II,7只),Klf4敲除高血压模型组(Klf4-SMKO+Ang II,7只)。在建模0、7、14、21、28 d分别测量模型组小鼠血压;28 d心脏超声检测心功能;收取小鼠心脏检测心脏质量/体质量比值;切片进行麦胚凝集素和天狼猩红染色,分别检测心肌细胞大小和心脏纤维化重塑。结果 高血压建模后Klf4-SMKO和Klf4-flox两组小鼠的血压无明显差异,心脏超声检测平滑肌细胞Klf4特异性敲除降低了高血压模型小鼠左心室质量。Klf4敲除显著降低了高血压引起的心质量/体质量比值增加,并且抑制了高血压造成的心肌细胞肥大和心脏血管周围纤维化。结论 血管平滑肌细胞KLF4缺失改善了高血压小鼠心脏病理性重塑。

Objective To investigate the regulatory effect of vascular smooth muscle cell Krüppel like factor 4(KLF4) on cardiac remodeling in mice with hypertension.Methods A mouse model of hypertension was established via subcutaneous infusion of angiotensin II(AngII) by using implanted osmotic pumps for 28 days,with a dose of 1 500 ng/(kg·min).We constructed the tamoxifen-induced vascular smooth muscle cell Klf4 specific knockout(Klf4-SMKO) mice.Thirteen Klf4-SMKO and thirteen Klf4-flox wild-type male mice,aged 9-10 weeks,were randomly divided into four groups:wild-type control group(Klf4-flox mice with saline infusion,n=6),Klf4-knockout control group(Klf4-SMKO mice with saline,n=6),wild-type hypertension group(Klf4-flox mice with Ang II infusion,n=7),and Klf4-knockout hypertension group(Klf4-SMKO mice with Ang II,n=7).Blood pressure of mice in hypertension groups were measured at day-0,7,14,21,and 28,respectively.Cardiac function was assessed with echocardiography.The ratio of heart weight to body weight was calculated,and the cross-sectional area of cardiomyocytes and cardiac fibrosis were detected by wheat germ agglutinin and Sirius red staining.Results The blood pressure exhibited no difference between the Klf4-SMKO and Klf4-flox hypertension groups.Echocardiography showed that smooth muscle Klf4 specific knockout decreased the left ventricular mass in mice with hypertension.Furthermore,Klf4 knockout significantly attenuated hypertension-induced increase of heart weight,as well as cardiomyocyte hypertrophy and perivascular fibrosis.Conclusions KLF4 deficiency in vascular smooth muscle cells ameliorates hypertension-induced pathological cardiac remodeling in mice.