Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin
Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin
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兰索拉唑通过阻断 β-连环蛋白的激活减轻压力超负荷引起的小鼠心脏肥大和心力衰竭
DOI：
10.1093/cvr/cvz016
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发表时间：
2020-01-01
影响因子：
10.8
通讯作者：
Liao, Yulin
中科院分区：
文献类型：
--
作者：
Lin, Hairuo;Li, Yang;Liao, Yulin
质子泵抑制剂（PPIs）被广泛应用于经皮冠状动脉介入治疗（PCI）患者预防胃出血，但PPIs是否对心脏有益存在争议。在这里，我们研究了兰索拉唑对心脏肥大和心力衰竭的影响，以及潜在的mechanism.Methods和结果成年雄性C57小鼠进行横向主动脉缩窄（TAC）或假手术，然后与兰索拉唑或车辆进行了5周的治疗。此外，在存在或不存在兰索拉唑的情况下，将培养的新生大鼠心室心肌细胞和成纤维细胞暴露于血管紧张素II。在TAC后5周，兰索拉唑给药小鼠的心脏重量/体重比低于未给药小鼠，肺重量/体重比也是如此，而兰索拉唑给药小鼠的左心室（LV）缩短分数以及LV压力的最大和最小变化率较高，沿着心脏纤维化较少。在培养的心肌细胞中，兰索拉唑抑制血管紧张素II诱导的蛋白质合成和肥大，以及抑制成纤维细胞增殖。兰索拉唑降低了TAC小鼠和血管紧张素II刺激的心肌细胞中磷酸化Akt、磷酸化糖原合成酶激酶3 β和活性β-连环蛋白的心肌水平。结论兰索拉唑通过抑制Akt/GSK 3 β/β-catenin通路的激活抑制心肌重构，而不依赖于H +/K +-ATP酶的抑制作用，这一发现可能为PPI减轻心肌重构的药理学作用提供了新的视角。
Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms.Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3 beta, and active beta-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active beta-catenin or knockdown of H+/K+-ATPase alpha-subunit, lansoprazole still significantly attenuated myocyte hypertrophy.Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3 beta/beta-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.