Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Acta Physiol (Oxf). 2023 Jun;238(2):e13964. doi: 10.1111/apha.13964. Epub 2023 Mar 31.
Hyperphosphatemia is associated with adverse cardiovascular outcomes in both the general population and patients with end-stage renal disease. We evaluated whether high inorganic phosphate (Pi) intake causes atrial remodeling and increased atrial fibrillation (AF) risk.
The 5/6 nephrectomized chronic kidney disease (CKD) mice were fed a high-Pi (2%) diet for 10 weeks. AF vulnerability was evaluated through transesophageal burst atrial pacing. Phosphoproteomic, Western blotting, and immunohistochemistry were used to evaluate the effects of high Pi in atrial fibroblasts, atrial myocytes, and HL-1 myocytes.
CKD and sham mice fed a high-Pi diet exhibited increased AF vulnerability, atrial fibrosis, and oxidative stress compared with mice fed a normal diet. Compared with normal (1 mM) Pi, high (2 mM) Pi significantly increased the activity of atrial fibroblasts and mitochondrial oxidative stress. Phosphoproteomic analysis revealed that compared with normal Pi, high Pi considerably increased the phosphorylation of intracellular proteins in atrial fibroblasts, including proteins related to NF-κB signaling and STAT3. Inhibition of NF-κB, STAT3, and Nox4 by small interfering RNA reduced the high-Pi-induced expression of collagen. In HL-1 myocytes, the high Pi induced the degradation of myofibril proteins and hyperphosphorylation of RyR2, which was abolished by Nox4 and CaMKII inhibition. Switching back to a normal-Pi diet improved the atrial abnormalities induced by high-Pi diet.
High-Pi intake causes atrial structural and electrical remodeling and increases AF vulnerability, which is mediated through STAT3/NF-κB signaling and oxidative stress. High dietary Pi intake can exert detrimental effects on atria and may increase AF risk.
高磷血症与普通人群和终末期肾病患者的不良心血管结局相关。我们评估了高无机磷（Pi）摄入是否会导致心房重构和增加心房颤动（AF）风险。
对 5/6 肾切除的慢性肾脏病（CKD）小鼠进行 10 周的高磷（2%）饮食喂养。通过食管超声心动图诱发的心房猝发刺激评估 AF 易感性。通过磷酸化蛋白质组学、Western blot 和免疫组化来评估高 Pi 对心房成纤维细胞、心房肌细胞和 HL-1 心肌细胞的影响。
与正常饮食组相比，高磷饮食喂养的 CKD 和假手术组小鼠的 AF 易感性、心房纤维化和氧化应激增加。与正常 Pi（1mM）相比，高 Pi（2mM）显著增加了心房成纤维细胞的活性和线粒体氧化应激。磷酸化蛋白质组学分析显示，与正常 Pi 相比，高 Pi 显著增加了心房成纤维细胞中包括 NF-κB 信号和 STAT3 相关的细胞内蛋白的磷酸化。通过小干扰 RNA 抑制 NF-κB、STAT3 和 Nox4 减少了高 Pi 诱导的胶原表达。在 HL-1 心肌细胞中，高 Pi 诱导肌原纤维蛋白的降解和 RyR2 的过度磷酸化，Nox4 和 CaMKII 抑制可消除这种作用。切换回正常 Pi 饮食可改善高 Pi 饮食引起的心房异常。
高 Pi 摄入导致心房结构和电重构，并增加 AF 易感性，这是通过 STAT3/NF-κB 信号和氧化应激介导的。高膳食 Pi 摄入可能对心房产生有害影响，并可能增加 AF 风险。
