Interactions of SERCA2a and BMPRII in Vascular Disease

SERCA2a 和 BMPRII 在血管疾病中的相互作用

• 批准号: 10000208
• 负责人: Lahouaria HADRI
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000208
• 关键词: ATP2A2; Ablation; Adenoviruses; Affect; Animal Model; Apoptosis; Arteries; Attenuated; Binding; Biopsy; Blood Vessels; Ca(2+)-Transporting ATPase; Calcium; Cell Proliferation; Cells; Cessation of life; Chemicals; Chronic; Clinical; Complex; Dependovirus; Development; Disease; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Evaluation; Failure; Family; Fibrosis; Functional disorder; Gene Expression Regulation; Gene Transfer; Genes; Goals; Heart; Heart failure; Homeostasis; Human; Hypertrophy; Hypoxia; In Vitro; Inflammation; Investigation; KDR gene; Kinetics; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Light; Link; LoxP-flanked allele; Lung; Medial; Messenger RNA; Modality; Modeling; Monocrotaline; Mus; Muscle; Mutation; Myosin Heavy Chains; NOS3 gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Physiologic intraventricular pressure; Play; Proteins; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Pump; Rattus; Reticulum; Role; STAT3 gene; SU 5416; Sampling; Serotyping; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Spatial Distribution; Structure; Syndrome; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transforming Growth Factor beta; Transgenic Animals; Transgenic Organisms; Vascular Diseases; Vascular Proliferation; Vascular remodeling; Ventricular; aerosolized; arteriole; base; bone morphogenetic protein receptors; cell growth; cell motility; design; disease phenotype; endothelial dysfunction; experimental study; gene therapy; knock-down; loss of function; loss of function mutation; member; migration; mouse model; mutant; novel therapeutics; overexpression; premature; primary pulmonary hypertension; pulmonary arterial hypertension; restoration; targeted treatment; trafficking; treatment effect; vasoconstriction

Pulmonary arterial hypertension (PAH) is characterized by an increase of pulmonary vascular resistance leading to right ventricular overload and eventually to right ventricular failure and premature death. The pathological mechanisms underlying this condition remains incompletely understood. While the exact causes of PAH remain under investigation, it is widely recognized that the hallmarks of all forms of PH are sustained vasoconstriction, endothelium dysfunction and vascular remodeling. Remodeling of pulmonary arteries is characterized to varying degrees by thickening of the intimal and medial layer of muscular vessels resulting from proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) with alterations in Ca2+ homeostasis. Diverse loss-of-function mutations in the conical BMPR2 gene, a component of the transforming growth factor beta (TGFβ) family that plays a key role in cell growth and fibrosis, have been associated with the majority of familial and sporadic cases of PAH. We have shown that sarco(endo)plasmic reticulum Ca2+- ATPase 2a (SERCA2a) pump expression is decreased in small hypertrophied pulmonary arterioles from patients with PAH and in a rat model of monocrotaline (MCT)-induced PAH. We also found that SERCA2a expression is reduced in hypertrophied pulmonary arterial wall of patients with underlying BMPR2 mutations and in transgenic SM22-tet-BMPR2delx4 mice, with a SMC-specific mutant form of BMPR2, known to develop spontaneous PAH. Gene transfer of SERCA2a by an adenovirus resulted in decreased human PASMC proliferation and migration via a mechanism involving STAT3/NFAT signaling pathways. In addition, SERCA2a overexpression increased BMPR2, eNOS expression and activity and decreased STAT3/NFAT activity in hPAEC. In addition, selective pulmonary SERCA2a gene transfer using aerosolized adeno-associated virus serotype 1 (AAV1.SERCA2a) in MCT-PAH rat model attenuate pulmonary hypertension and RV hypertrophy, and increased eNOS and BMPR2 expression. Based upon the preliminary findings we contend there is cross talk between SERCA2a and BMPR2 with interdependent downstream signaling in pulmonary vascular that affects pulmonary vascular structural remodeling and suggest that SERCA2a gene transfer may modulate BMPR2 expression and/or dependent signaling pathways and therefore PAH phenotype. To test this hypothesis we will: 1) Characterize the link between SERCA2a and BMPR2 in pulmonary vascular cells. 2) Determine the effects of SERCA2-specific ablation in SMCs & ECs on PAH pathogenesis in a mouse model. And 3) Investigate the therapeutic effects of SERCA2a overexpression using chemically modified messenger RNA (modRNA) in transgenic animal models. The knowledge acquired through this proposal is significant because by modulating SERCA2a expression, we will characterize its key role in BMPR2 expression and signaling and therefore in pulmonary vascular remodeling and PAH phenotype, that may lead to the identification of new potential targets for therapeutic intervention to overcome the pathological feature of PAH.

肺动脉高压（PAH）的特征是肺血管阻力增加 导致右心室超负荷并最终导致右心室衰竭和过早死亡。的 这种疾病的病理机制仍然不完全清楚。虽然确切的原因是 尽管PAH的发病率仍在调查中，但人们普遍认为，所有形式的PH的特征都是持续的， 血管收缩、内皮功能障碍和血管重塑。肺动脉重塑是 以不同程度的肌血管内膜和中层增厚为特征， 肺动脉平滑肌细胞（PASMCs）的增殖和迁移与Ca 2+的变化 体内平衡。锥形BMPR 2基因的多种功能丧失突变， 生长因子β（TGFβ）家族在细胞生长和纤维化中起关键作用，已与 大多数家族性和散发性PAH病例。我们已经表明，肌（内）质网Ca 2 +- ATP酶2a（SERCA 2a）泵的表达在肺小动脉肥大中减少， PAH患者和野百合碱（MCT）诱导的PAH大鼠模型。我们还发现SERCA 2a BMPR 2基因突变患者肥大肺动脉壁表达减少 在转基因SM 22-tet-BMPR 2delx 4小鼠中，具有SMC特异性突变形式的BMPR 2，已知其发展为 自发性PAH。腺病毒介导的SERCA 2a基因转移导致人PASMC减少 通过涉及STAT 3/NFAT信号传导途径的机制来抑制增殖和迁移。此外，SERCA 2a 过表达增加BMPR 2、eNOS的表达和活性，降低STAT 3/NFAT的活性。 hPAEC。此外，使用雾化腺相关病毒的选择性肺SERCA 2a基因转移 血清型1（AAV1.SERCA2a）在MCT-PAH大鼠模型中减轻肺动脉高压和RV肥大， 增加eNOS和BMPR 2的表达。根据初步调查结果，我们认为 SERCA 2a和BMPR 2在肺血管中相互依赖下游信号转导 影响肺血管结构重塑，并提示SERCA 2a基因转移可调节 BMPR 2表达和/或依赖性信号传导途径，因此PAH表型。为了验证这一 我们将：1）表征肺血管细胞中SERCA 2a和BMPR 2之间的联系。（二） 确定SMC和EC中SERCA 2特异性消融对小鼠模型中PAH发病机制的影响。 用化学修饰的信使蛋白研究SERCA 2a过表达的治疗作用 RNA（modRNA）在转基因动物模型中的作用。通过这一提议获得的知识意义重大 因为通过调节SERCA 2a表达，我们将表征其在BMPR 2表达中的关键作用， 信号传导，因此在肺血管重塑和PAH表型中，这可能导致 确定新的潜在治疗干预靶点，以克服PAH的病理特征。

项目成果

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• DOI: 10.3389/fcvm.2022.855181
• 发表时间: 2022
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6

Spaceflight-Associated Changes of snoRNAs in Peripheral Blood Mononuclear Cells and Plasma Exosomes-A Pilot Study.

• DOI: 10.3389/fcvm.2022.886689
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Rai, Amit Kumar;Rajan, K. Shanmugha;Bisserier, Malik;Brojakowska, Agnieszka;Sebastian, Aimy;Evans, Angela C.;Coleman, Matthew A.;Mills, Paul J.;Arakelyan, Arsen;Uchida, Shizuka;Hadri, Lahouaria;Goukassian, David A.;Garikipati, Venkata Naga Srikanth
• 通讯作者: Garikipati, Venkata Naga Srikanth