Department of Cardiology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Neurology, the First Afliated Hospital of Zhengzhou University, Zhengzhou, China.
Cell Death Dis. 2020 Feb 6;11(2):96. doi: 10.1038/s41419-020-2296-4.
Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8 mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.
抗菌肽（Cathelicidin-related antimicrobial peptide，CRAMP）是一种抗菌肽，据报道可预防心肌缺血/再灌注损伤。然而，CRAMP 对压力超负荷引起的心肌肥厚的影响尚不清楚。本研究探讨了 CRAMP 对心肌肥厚的作用。通过主动脉缩窄手术诱导心肌肥厚小鼠模型。手术后 7 天，通过腹腔注射 mCRAMP（8mg/kg/d）治疗 7 周。通过肥大反应和纤维化水平以及心功能评估心肌肥厚。还通过注射 AAV9-shCRAMP 敲低小鼠心脏中的 CRAMP。CRAMP 水平在重塑心脏中先增加后减少，在血管紧张素 II 刺激的内皮细胞中而不是在心肌细胞和成纤维细胞中。mCRAMP 可预防压力超负荷引起的心脏重塑过程，而 CRAMP 敲低加速了这一过程。mCRAMP 减轻肥厚心脏中的炎症反应和氧化应激，而 mCRAMP 缺乏则恶化压力超负荷引起的炎症反应和氧化应激。mCRAMP 抑制血管紧张素 II 刺激的新生大鼠心肌细胞肥大反应和氧化应激，但对内皮细胞中的血管紧张素 II 诱导的炎症反应和氧化应激无帮助。机制上，我们发现 mCRAMP 通过直接与 IGFR1 结合激活 IGFR1/PI3K/AKT 通路来抑制心脏肥大反应。AKT 敲除小鼠完全逆转了 mCRAMP 的抗肥大作用，但不影响其抗氧化作用。我们还发现 mCRAMP 通过激活 TLR9/AMPKa 通路改善心脏氧化应激。TLR9 敲除小鼠实验证实了这一点，其中 TLR9 敲除部分逆转了 mCRAMP 的抗肥大作用，完全抵消了 mCRAMP 的抗氧化作用。总之，mCRAMP 通过激活心肌细胞中的 IGFR1/PI3K/AKT 和 TLR9/AMPKa 通路来预防压力超负荷引起的心肌肥厚。
