Cardioprotection and uncoupling myofibroblast-myocyte communications

心脏保护和解偶联肌成纤维细胞-肌细胞通讯

• 批准号: 10430147
• 负责人: Simon James Conway
• 金额: $ 39.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430147
• 关键词: Ablation; Action Potentials; Acute; Acute myocardial infarction; Adrenergic Agents; Agonist; Angiotensin II; Angiotensin II Receptor; Arrhythmia; Biological Assay; CCL2 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Cessation of life; Chronic; Collagen; Communication; Connexin 43; Connexins; Coupling; Data; Electrophysiology (science); Enhancers; Enterobacteria phage P1 Cre recombinase; Exhibits; Fibrosis; Functional disorder; Gap Junctions; Heart; Heart Injuries; Histologic; Hypertrophy; Image; Immunohistochemistry; In Vitro; Infusion procedures; Injury; Isoproterenol; Mediating; Messenger RNA; Molecular; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Myofibroblast; Pathologic; Patients; Performance; Play; Population; Predisposition; Prevalence; Property; Reporter; Role; Shapes; Signal Transduction; Site; Stretching; Structure; Tamoxifen; Testing; Transforming Growth Factor beta; Up-Regulation; Ventricular; cardioprotection; chemokine receptor; coronary fibrosis; cytokine; data modeling; experimental study; genetic manipulation; heart rhythm; in vivo; injured; monocyte chemoattractant protein 1 receptor; mouse model; novel; paracrine; periostin; pressure; prevent; profibrotic cytokine; recombinase; response; tool; voltage

PROJECT SUMMARY/ABSTRACT In response to damage, pathological cardiac remodeling frequently manifests as myocardial hypertrophy, fibrosis, contractile dysfunction and/or increased arrhythmia vulnerability. Myofibroblasts (Mfbs) are not normally present in the working myocardium but accumulate in large numbers in the injured heart. Hypersecretion of collagen and paracrine factors from activated Mfbs results in the formation of electrically insulating septa and ionic remodeling of cardiomyocytes (CMs), respectively, promoting arrhythmia. Besides their barrier and paracrine function, preliminary experiments using intravital voltage imaging and immunohistochemistry, suggest the intriguing possibility that Mfbs influence the functional properties of fibrotically remodeled myocardium via direct electrotonic interactions with surrounding CMs via gap junctions composed of cell-to-cell Connexin(Cx)43 subunits. Preliminary mouse modeling data also revealed that chronic systemic infusion of β-adrenergic or angiotensin-II receptor agonists, as well as acute myocardial infarction (MI) result in Mfb-restricted misexpression of Cx43, a stretch-induced profibrotic cytokine Ccl2 (MCP-1) and profibrotic matricellular Periostin (Postn) coincident with pathological remodeling. Likewise, in patients with acute MI or pressure overload, POSTN and MCP-1 are robustly upregulated and Cx43 (GJA1) distribution is perturbed. Cx43, the principal gap junction protein responsible for action potential propagation in ventricles, is often mis-expressed in hypertrophied and ischemic patient hearts. We and others have demonstrated that Cx43 is also present in the pathological Mfb population, and additional preliminary data revealed Ccl2 is transcribed in Mfbs (whereas its receptor Ccr2 is in CMs). Endogenous Postn functionally promotes cardiac fibrosis/ventricular stiffness, as surviving Postn nulls exhibit less fibrosis and better function after MI. Moreover, we generated a unique 3.9kb-driven Postn enhancer reporter line that drives Cre-recombinase expression only in Mfbs in injured hearts (designated Postn-Cre). Thus, this is a most useful tool for genetic manipulation of cardiac activated injury-site Mfbs. However, the actual role that electrical coupling in Postn-expressing Mfb-lineage plays and the mechanism underlying Mfb-CM interactions during pathological remodeling remain unknown. Thus, three interrelated aims are proposed to examine these preliminary data. Aim 1 will test the hypothesis that uncoupling Mfb-CM electrical signaling via Mfb-restricted cKO of Cx43 prevents adverse cardiac remodeling. Aim 2 will test whether Mfb-restricted Cx43 cKO offers arrhythmia protection. Aim 3 will determine if Mfb-restricted loss of the Ccl2 cytokine ameliorates adjacent CM contractile dysfunction.

项目摘要/摘要 作为对损伤的反应，病理性心脏重构通常表现为心肌肥大， 纤维化、收缩功能障碍和/或心律失常易感性增加。肌成纤维细胞(Mfbs)不是正常的 存在于工作心肌中，但在受伤的心脏中大量积累。高分泌激素 活化的Mfbs中的胶原和旁分泌因子导致电绝缘隔膜的形成和 心肌细胞的离子重塑(CMS)分别促进心律失常。除了他们的障碍和 利用活体电压成像和免疫组织化学的初步实验表明，旁分泌功能 Mfbs通过影响纤维重塑心肌的功能特性的有趣可能性 通过由细胞间连接蛋白(CX)43组成的缝隙连接与周围CMS的直接电渗性相互作用 亚单位。初步的小鼠模型数据还显示，慢性全身注射β-肾上腺素能或 血管紧张素-II受体激动剂和急性心肌梗死(MI)导致MFB限制性错误表达 Cx43，一种牵张诱导的促纤维化细胞因子CCL2(MCP-1)和促纤维化基质细胞周膜蛋白(Postn) 与病理重塑相吻合。同样，在急性心肌梗死或压力超负荷的患者中，POSTN和 MCP-1显著上调，Cx43(GJA1)分布受到干扰。Cx43，主要缝隙结 负责在脑室中传播动作电位的蛋白质，通常在肥厚的和 缺血患者的心脏。我们和其他人已经证明，Cx43也存在于病理性MFB中 更多的初步数据表明CCL2在Mfbs中转录(而其受体CCR2在 CMS)。内源性Postn作为存活的Postn功能促进心肌纤维化/心室僵硬 心肌梗死后纤维化较轻，功能较好。此外，我们还生成了一个独特的3.9kb驱动的Postn增强子 仅在受损心脏的Mfbs中驱动Cre-重组酶表达的报道株(命名为Postn-Cre)。因此， 这对于心脏激活损伤部位Mfbs的基因操作是最有用的工具。然而，实际的作用是 表达Postn的MFB谱系中的电耦合及其机制 病理重塑过程中的相互作用仍不清楚。因此，提出了三个相互关联的目标，以 检查这些初步数据。目标1将检验这样的假设，即解偶联MFB-CM电信号通过 Cx43的MFB限制性CKO可防止不利的心脏重构。AIM 2将测试受MFB限制的Cx43 CKO提供心律失常保护。Aim 3将确定MFB限制的CCL2细胞因子丢失是否改善 邻近心肌收缩功能障碍。

项目成果

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

• DOI: 10.1007/s00395-021-00846-y
• 发表时间: 2021-02-09
• 期刊: Basic research in cardiology
• 影响因子: 9.5
• 作者: Dufeys C;Daskalopoulos EP;Castanares-Zapatero D;Conway SJ;Ginion A;Bouzin C;Ambroise J;Bearzatto B;Gala JL;Heymans S;Papageorgiou AP;Vinckier S;Cumps J;Balligand JL;Vanhaverbeke M;Sinnaeve P;Janssens S;Bertrand L;Beauloye C;Horman S
• 通讯作者: Horman S

SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation.

• DOI: 10.1038/s41419-023-05982-y
• 发表时间: 2023-07-19
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Kawaguchi, Satoshi;Moukette, Bruno;Sepulveda, Marisa N.;Hayasaka, Taiki;Aonuma, Tatsuya;Haskell, Angela K.;Mah, Jessica;Liangpunsakul, Suthat;Tang, Yaoliang;Conway, Simon J.;Kim, Il-man
• 通讯作者: Kim, Il-man

Cracd Marks the First Wave of Meiosis during Spermatogenesis and Is Mis-Expressed in Azoospermia Mice.

• DOI: 10.3390/jdb8030021
• 发表时间: 2020-09-18
• 期刊: Journal of developmental biology
• 影响因子: 2.7
• 作者: Snider PL;Simmons O;Conway SJ
• 通讯作者: Conway SJ