Matsushita Naoko, Ishida Nanae, Ibi Miho, Saito Maki, Sanbe Atsushi, Shimojo Hisashi, Suzuki Satoshi, Koepsell Hermann, Takeishi Yasuchika, Morino Yoshihiro, Taira Eiichi, Sawa Yohei, Hirose Masamichi
Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine.
Department of Molecular and Cellular Pharmacology, Iwate Medical University School of Pharmaceutical Sciences.
Int Heart J. 2018 Sep 26;59(5):1123-1133. doi: 10.1536/ihj.17-565. Epub 2018 Aug 11.
Increased gene expression levels of sodium-glucose cotransporter 1 (SGLT1) are associated with hypertrophic and ischemic cardiomyopathy. However, it remains unclear whether chronic pressure overload increases SGLT1 expression, which in turn induces hypertrophic cardiomyopathy. We hypothesized that pressure overload could increase SGLT1 gene expression, leading to the development of hypertrophic cardiomyopathy.To create pressure overload-induced cardiomyopathy, transverse aortic constriction (TAC) was performed in SGLT1-deficient (SGLT1) and wild-type (WT) mice. Six weeks after surgery, all mice were investigated. We observed a reduction of left ventricular fractional shortening and left ventricular dilatation in TAC-operated WT but not in TAC-operated SGLT1 mice. SGLT1, interleukin 18, connective tissue growth factor, and collagen type 1 gene expression levels were increased in TAC-operated WT mouse hearts compared with that of sham-operated WT mouse hearts. Moreover, heart/body weight ratio and ventricular interstitial fibrosis were increased in TAC-operated WT mice compared with that of sham-operated WT mice. Interestingly, these factors did not increase in TAC-operated SGLT1 mice compared with that of sham-operated WT and SGLT1 mice. Phenylephrine, an adrenergic α receptor agonist, caused cardiomyocyte hypertrophy in neonatal WT mouse hearts to a significantly larger extent than in neonatal SGLT1 mouse hearts.In conclusion, the results indicate that chronic pressure overload increases SGLT1 and IL-18 gene expressions, leading to the development of hypertrophic cardiomyopathy. These results make SGLT1 a potential candidate for the therapeutic target for hypertension-induced cardiomyopathy.
钠-葡萄糖协同转运蛋白1（SGLT1）基因表达水平升高与肥厚型和缺血性心肌病相关。然而，慢性压力超负荷是否会增加SGLT1表达进而诱发肥厚型心肌病仍不清楚。我们推测压力超负荷会增加SGLT1基因表达，导致肥厚型心肌病的发生。为了制造压力超负荷诱导的心肌病，在SGLT1基因缺陷（SGLT1）小鼠和野生型（WT）小鼠中进行了横向主动脉缩窄（TAC）手术。术后六周，对所有小鼠进行研究。我们观察到，接受TAC手术的WT小鼠左心室短轴缩短率降低和左心室扩张，但接受TAC手术的SGLT1小鼠未出现这种情况。与假手术的WT小鼠心脏相比，接受TAC手术的WT小鼠心脏中SGLT1、白细胞介素18、结缔组织生长因子和I型胶原基因表达水平升高。此外，与假手术的WT小鼠相比，接受TAC手术的WT小鼠心脏/体重比和心室间质纤维化增加。有趣的是，与假手术的WT和SGLT1小鼠相比，接受TAC手术的SGLT1小鼠中这些因素并未增加。肾上腺素能α受体激动剂去氧肾上腺素引起新生WT小鼠心脏的心肌细胞肥大，其程度明显大于新生SGLT1小鼠心脏。总之，结果表明慢性压力超负荷会增加SGLT1和IL-18基因表达，导致肥厚型心肌病的发生。这些结果使SGLT1成为高血压诱导性心肌病治疗靶点的潜在候选者。
