Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction.
Chondroitin sulfate proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction.
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DOI：
10.7554/elife.78387
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发表时间：
2022-05-23
期刊：
影响因子：
7.7
通讯作者：
Habecker, Beth A.
中科院分区：
文献类型：
--
作者：
Blake, Matthew R.;Parrish, Diana C.;Staffenson, Melanie A.;Sueda, Shanice;Woodward, William R.;Habecker, Beth A.
关键词：
心肌缺血/再灌注诱导的心肌梗死（MI）后，心脏交感神经去支配是由心脏瘢痕中的硫酸软骨素蛋白聚糖（CSPGs）维持的。去神经支配可预测人类心脏性猝死的风险。阻断CSPG信号可以恢复交感轴突向心脏瘢痕的生长，降低心律失常的易感性。CSPGs对轴突生长的抑制可能取决于糖胺聚糖（CS-GAG）侧链的磺化状态。在n-乙酰半乳糖胺的第4 （4S）和第6 （6S）位置串联磺化CS-GAGs抑制几种中枢神经元的生长，但我们不知道磺化在周围神经再生中是否同样重要。我们研究了CSPG磺化是否会阻止心肌梗死后交感神经轴突的生长。用4-磺化酶Arylsulfatase-B （ARSB）减少4S能比CSPGs增强解离大鼠交感神经元的生长。同样，用ARSB减少4S可以恢复小鼠交感神经节与心脏瘢痕组织共培养的轴突生长。我们量化了负责添加和去除硫酸化的酶，发现心肌梗死后CHST15 （4S依赖性6-硫转移酶）上调，ARSB下调。这提示了心肌疤痕中硫酸化CSPGs的产生和维持机制。我们通过心肌梗死后短暂siRNA敲低Chst15，在体内降低4S、6S CS-GAGs，发现减少4S、6S可恢复心脏瘢痕中酪氨酸羟化酶（TH）阳性的交感神经纤维。再神经移植可减少异丙肾上腺素引起的心律失常。我们的研究结果表明，心肌梗死后调节cspg -硫酸化可能是促进心脏瘢痕交感神经再生和减少心肌梗死后心律失常的治疗靶点。
Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don’t know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.
影响因子：
2
作者：
Tian, Yuan;Koganti, Tejaswi;Yao, Zhihao;Cannon, Presley;Shah, Punit;Pietrovito, Laura;Modesti, Alessandra;Aiyetan, Paul;DeLeon-Pennell, Kristine;Ma, Yonggang;Halade, Ganesh V.;Hicks, Chindo;Zhang, Hui;Lindsey, Merry L.
通讯作者：
Lindsey, Merry L.