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.

项目概要/摘要 为了应对损伤，病理性心脏重塑经常表现为心肌肥厚， 纤维化、收缩功能障碍和/或心律失常脆弱性增加通常不会发生。 存在于工作的心肌中，但在受伤的分泌过多的心脏中大量积聚。 活化的 Mfb 中的胶原蛋白和旁分泌因子导致电绝缘隔膜和 心肌细胞（CM）的离子重塑，除了其屏障和心律失常之外，还分别促进。 旁分泌功能，使用活体电压成像和免疫组织化学的初步实验表明 Mfbs 通过以下方式影响纤维化重塑心肌的功能特性，这一有趣的可能性 通过由细胞间连接蛋白 (Cx)43 组成的间隙连接与周围 CM 进行直接电紧张相互作用 初步的小鼠模型数据还表明，长期全身输注β-肾上腺素能或 血管紧张素 II 受体激动剂以及急性心肌梗死 (MI) 会导致 Mfb 限制性错误表达 Cx43、一种拉伸诱导的促纤维化细胞因子 Ccl2 (MCP-1) 和促纤维化基质细胞骨膜蛋白 (Postn) 同样，在患有急性心肌梗死或压力超负荷的患者中，POSTN 和 MCP-1 显着上调，Cx43 (GJA1) 分布受到干扰，Cx43（主要间隙连接）。 负责心室动作电位传播的蛋白质，经常在肥大和肥大的细胞中错误表达 我们和其他人已经证明 Cx43 也存在于病理性 Mfb 中。 人群，额外的初步数据显示 Ccl2 在 Mfbs 中转录（而其受体 Ccr2 在 内源性 Postn 功能性地促进心脏纤维化/心室僵硬，因为存活的 Postn 无效。 MI 后表现出更少的纤维化和更好的功能此外，我们生成了独特的 3.9kb 驱动的 Postn 增强子。 仅在受伤心脏的 Mfb 中驱动 Cre 重组酶表达的报告基因线（称为 Postn-Cre）。 这是对心脏激活损伤部位 Mfb 进行基因操作的最有用的工具，但其实际作用却很有限。 Postn 表达 Mfb 谱系中的电耦合以及 Mfb-CM 的潜在机制 病理重塑过程中的相互作用仍然未知，因此，提出了三个相互关联的目标。 检查这些初步数据，目的 1 将测试通过解耦 Mfb-CM 电信号传导的假设。 Mfb 限制的 Cx43 cKO 可预防不良心脏重塑。目标 2 将测试 Mfb 限制的 Cx43 是否存在。 cKO 提供心律失常保护，目标 3 将确定 Mfb 限制的 Ccl2 细胞因子丢失是否会改善。 邻近 CM 收缩功能障碍。

项目成果

Optogenetics: Background, Methodological Advances and Potential Applications for Cardiovascular Research and Medicine.

光遗传学：心血管研究和医学的背景、方法学进展和潜在应用。

• 发表时间: 2019
• 作者: Joshi, Jyotsna;Rubart, Michael;Zhu, Wuqiang
• 通讯作者: Zhu, Wuqiang

Periostin-related progression of different types of experimental pulmonary hypertension: A role for M2 macrophage and FGF-2 signalling.

不同类型实验性肺动脉高压的骨膜素相关进展：M2 巨噬细胞和 FGF-2 信号传导的作用。

• 发表时间: 2022-07
• 作者: Yoshida, Takashi;Nagaoka, Tetsutaro;Nagata, Yuichi;Suzuki, Yoshifumi;Tsutsumi, Takeo;Kuriyama, Sachiko;Watanabe, Junko;Togo, Shinsaku;Takahashi, Fumiyuki;Matsushita, Masakazu;Joki, Yusuke;Konishi, Hakuoh;Nunomura, Satoshi;Izuhara, Kenji;Conw
• 通讯作者: Conw

Armadillo-like helical domain containing-4 is dynamically expressed in both the first and second heart fields.

含有-4的犰狳样螺旋结构域在第一和第二心区动态表达。

• 发表时间: 2019
• 作者: Conway, Simon J;McConnell, Reagan;Simmons, Olga;Snider, Paige L
• 通讯作者: Snider, Paige L

NF-κB activation in cardiac fibroblasts results in the recruitment of inflammatory Ly6Chi monocytes in pressure-overloaded hearts.

心脏成纤维细胞中的 NF-κB 激活导致压力超负荷的心脏中炎症性 Ly6Chi 单核细胞的募集。

• 发表时间: 2021-10-12
• 影响因子: 7.3
• 作者: Abe, Hajime;Tanada, Yohei;Omiya, Shigemiki;Podaru, Mihai;Murakawa, Tomokazu;Ito, Jumpei;Shah, Ajay M;Conway, Simon J;Ono, Masahiro;Otsu, Kinya
• 通讯作者: Otsu, Kinya

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

肌成纤维细胞中的 AMPKα1 缺失通过连接蛋白 43 机制加剧心肌梗死后纤维化。

• 发表时间: 2021
• 影响因子: 9.5
• 作者: Dufeys, Cécile;Daskalopoulos, Evangelos;Castanares;Conway, Simon J;Ginion, Audrey;Bouzin, Caroline;Ambroise, Jérôme;Bearzatto, Bertrand;Gala, Jean;Heymans, Stephane;Papageorgiou, Anna;Vinckier, Stefan;Cumps
• 通讯作者: Cumps