Kambara Takahiro, Shibata Rei, Ohashi Koji, Matsuo Kazuhiro, Hiramatsu-Ito Mizuho, Enomoto Takashi, Yuasa Daisuke, Ito Masanori, Hayakawa Satoko, Ogawa Hayato, Aprahamian Tamar, Walsh Kenneth, Murohara Toyoaki, Ouchi Noriyuki
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Mol Cell Biol. 2015 Jun;35(12):2173-85. doi: 10.1128/MCB.01518-14. Epub 2015 Apr 13.
Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/AMPK-dependent mechanisms.
肥胖是心血管疾病的一个风险因素。C1q/肿瘤坏死因子相关蛋白9（CTRP9）是一种脂肪因子，其表达会因肥胖而下调。我们通过功能丧失性基因操作研究了CTRP9在心脏损伤中的作用，并确定了该脂肪因子下游的受体介导信号通路。12周龄的CTRP9基因敲除（CTRP9-KO）小鼠在基础条件下与野生型（WT）小鼠没有区别。与WT小鼠相比，腹腔注射脂多糖（LPS）后，CTRP9-KO小鼠的左心室收缩功能障碍加剧。与WT小鼠相比，给CTRP9-KO小鼠注射LPS还导致心脏中促炎细胞因子和氧化应激标志物的表达增加。同样，与WT小鼠相比，CTRP9-KO小鼠在缺血再灌注后的缺血心脏中梗死面积增加，炎症介质表达升高。用CTRP9蛋白处理心肌细胞可抑制LPS诱导的促炎基因表达，而这种抑制作用可通过阻断AMPK或敲除脂联素受体I（AdipoR1）来逆转。全身性给予CTRP9可减轻LPS诱导的WT小鼠心脏功能障碍，但对表达AMPK显性负性突变体的肌肉特异性转基因小鼠或AdipoR1基因敲除小鼠无效。CTRP9通过AdipoR1/AMPK依赖性机制抑制炎症反应，从而保护心脏免受病理刺激引起的急性损伤。
