Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy.
Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy.
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DOI：
10.1016/j.ijcard.2021.08.015
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发表时间：
2021-08
影响因子：
3.5
通讯作者：
I. Stadiotti;A. Di Bona;Chiara Assunta Pilato;A. Scalco;A. Guarino;Barbara Micheli;M. Casella;C. Tondo;S. Rizzo;K. Pilichou;G. Thiene;A. Frigo;G. Pompilio;C. Basso;E. Sommariva;M. Mongillo;T. Zaglia
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作者：
I. Stadiotti;A. Di Bona;Chiara Assunta Pilato;A. Scalco;A. Guarino;Barbara Micheli;M. Casella;C. Tondo;S. Rizzo;K. Pilichou;G. Thiene;A. Frigo;G. Pompilio;C. Basso;E. Sommariva;M. Mongillo;T. Zaglia
背景致心律失常性心肌病（ArrhythmogenicCardiomyopathy，AC）是一种家族性心脏病，主要由桥粒基因突变引起. AC心脏显示纤维脂肪心肌替代，这有利于与压力相关的危及生命的心律失常，主要发生在年轻人和运动员中。AC缺乏有效的治疗方法，因为其发病机制知之甚少。最近，我们发现心脏间充质基质细胞（cMSCs）有助于人类AC心脏的脂肪组织，尽管潜在的机制尚不清楚。目的我们假设交感神经递质神经肽Y（NPY）参与了人类AC中cMSCs的脂肪形成。来自健康对照和AC患者的心肌活检，使用现有药物干扰预测的AC机制。交感神经支配检查在人类尸检心脏样本，和NPY血浆水平测定在健康和AC subjects.ResultsAC cMSCs表达较高水平的前脂肪形成的同种型的NPY受体（即Y1-R，Y 5-R）。同样，NPY促进AC cMSCs的脂肪形成，这被FDA批准的Y1-R和Y 5-R拮抗剂阻断。AC相关的PKP 2减少直接导致cMSCs中的NPY依赖性脂肪形成。在支持的参与交感神经元（SNs）和NPY在AC心肌重塑，患者有升高的血浆NPY水平，在人类AC心脏，SNs积累在脂肪区，并接近cMSCs.ConclusionsIndependently从疾病的起源，AC导致cMSCs有针对性的增益响应NPY，从而导致脂肪生成增加，从而发挥作用，在AC心肌重塑。
BackgroundArrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear.PurposeWe hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC.MethodsFor translation of our findings, we combinedin vitrocytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects.ResultsAC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e.Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs.ConclusionsIndependently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling.