Ac-SDKP in the Treatment of Cardiac Dysfunction in Hypertension or Ischemic

Ac-SDKP 治疗高血压或缺血性心脏功能障碍

• 批准号: 10336561
• 负责人: NOUR-EDDINE RHALEB
• 金额: $ 47.45万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336561
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; Address; Adult; Affect; Angioneurotic Edema; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Anterior; Apoptosis; Blood Pressure; Blood capillaries; Calcium; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cells; Cessation of life; Collagen; Congestive Heart Failure; Conscious; Coronary; Coronary Arteriosclerosis; Coughing; Data; Dysgeusia; Echocardiography; Electrocardiogram; Endothelial Cells; Endothelium; Enzymes; Exanthema; Female; Fibroblasts; Fibrosis; Foundations; Gene Deletion; Genetic; Half-Life; Healthcare; Heart; Heart Diseases; Heart Injuries; Heart Rate; Heart failure; Heat shock proteins; Hypertension; Hypotension; Immunoblotting; Immunohistochemistry; Impairment; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Knock-out; Knockout Mice; Lead; Left; Ligation; Measurement; Measures; Meprin; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; Myocardial dysfunction; Myocardium; N-terminal; Organ; Oxidative Stress; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Polymerase Chain Reaction; Population; Production; Proto-Oncogene Proteins c-akt; Radioimmunoassay; Relaxation; Replacement Therapy; Reporting; Resistance; Reverse Transcription; Risk Factors; Role; Side; Signal Transduction; Structure; Techniques; Telemetry; Testing; Thymosin; Time; Tissues; United States; Western World; Wild Type Mouse; Work; analog; angiogenesis; cardioprotection; care burden; conditional knockout; coronary fibrosis; density; disability; dosage; endoplasmic reticulum stress; enzyme activity; eplerenone; experimental group; heart function; hyperkalemia; improved; in vivo; injured; lysylproline; male; mouse model; neovascularization; novel therapeutic intervention; premature; pressure; prolyl oligopeptidase; protective effect; recruit; side effect; thymosin beta(4); tool; transcription factor CHOP

Hypertension is a major health care burden in the United States, affecting 1 in 3 adults. Hypertension is associated with concomitant coronary artery disease with myocardial infarction (MI) and heart failure (HF). In this study, we will define how N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) protects cardiac structure and function in a mouse model of HF that will be induced in two models [angiotensin II (Ang II) hypertension- or permanent left anterior descending coronary ligation (LAD)]. We and others reported that Ang II-induced hypertension or LAD resulted in HF associated with cardiac structural remodeling and impaired function. Ac- SDKP is successively produced from thymosin 4 (T4) by two enzymes, meprin  and prolyl oligopeptidase (POP). Circulating and tissue Ac-SDKP depends on the angiotensin converting enzyme (ACE) activity, since Ac- SDKP is mainly degraded by the N-terminal active side of ACE (ACE-N). ACEi are first-line drugs to treat HF. ACEi have strong side effects such as hypotension, cough, rash, angioneurotic edema, hyperkalemia, and dysgeusia, whereas Ac-SDKP has none, even at high dosages (up to 48 mg/kg/d). Also, Ac-SDKP is down- regulated in the myocardium of dogs and patients with chronic HF. Whether and how Ac-SDKP therapy could rescue hypertension- or LAD-induced cardiac complications remain to be elucidated. Increasing circulating Ac- SDKP not only inhibited fibrosis and mediators of inflammatory cell infiltration into the injured myocardium, but it also improved cardiac function in mice with LAD or hypertension (preliminary data). We have found that Ac- SDKP inhibits endoplasmic reticulum (ER) stress in cardiac fibroblasts in vitro and in mice with MI and restores phosphor-AKT in hypertensive hearts. Activation of ER stress is detrimental to the endothelium, cardiac fibroblasts, and cardiomyocytes. These findings set the scientific premise of this work, providing foundational work that Ac-SDKP represents a beneficial supplement to the existing cardiac pharmacotherapy. Our central hypothesis is that Ac-SDKP protects and potentiates cardiac protection against heart failure via the inhibition of ER stress. We propose to use the mouse model of heart failure induced by hypertension or LAD to address the following 2 two aims: ( 1) we will determine whether Ac-SDKP protects the heart and provides additional cardiac protective effects to ARBs, ACEi, or eplerenone in mice with MI or hypertension, ( 2) and we will demonstrate that Ac-SDKP improves cardiac function in mice with hypertension or LAD by inhibiting the detrimental ER stress via the PI3K/AKT pathway. A number of conditional and tissue-specific knockout female and male mice will be employed. A team with significant expertise is recruited for this project, which will apply a combination of state-of-the-art in vivo, cell and molecular techniques including measurements of cardiac remodeling and function by echocardiography in non-anesthetized mice and radiotelemetry, which can detect the blood pressure, the electrocardiogram, and the heart rate of conscious mice. These studies will help define the cause-effect relationship between Ac-SDKP and HF and its mechanism towards the protection from HF.

高血压是美国的主要医疗保健伯恩，影响三分之一的成年人。高血压是 与心肌梗塞（MI）和心力衰竭（HF）伴随冠状动脉疾病有关。 这项研究，我们将定义N-乙酰基 - 甲基甲基 - 乙酰基 - 胆囊 - 丙酸酯（AC-SDKP）如何保护心脏结构和 HF小鼠模型中的功能将在两个模型中诱导[血管紧张素II（ANG II）高血压或 永久左前降冠状结扎（LAD）]。我们和其他人报告Ang II引起的 高血压或LAD导致HF与心脏结构重塑和功能受损相关。 ac SDKP由两种酶，meprin和prolyl寡肽酶成功从胸腺素4（T4）成功产生 （流行音乐）。循环和组织AC-SDKP取决于血管紧张素转化酶（ACE）活性，因为AC- SDKP主要由ACE（ACE-N）的N端活动侧降解。 ACEI是治疗HF的一线药物。 ACEI具有强烈的副作用，例如低血压，咳嗽，皮疹，阴离子性水肿，高钾血症和 dysgeusia，而AC-SDKP也没有，即使在高剂量下（高达48 mg/kg/d）。另外，AC-SDKP降低 - 在狗和慢性HF患者的心肌中受到调节。 AC-SDKP疗法是否以及如何 救援高血压或LAD引起的心脏并发症仍有待阐明。增加循环的ac- SDKP不仅抑制纤维化和炎症细胞介导子浸润到受伤的心肌中，而且还 还改善了使用LAD或高血压（初步数据）的小鼠心脏功能。我们发现Ac- SDKP抑制心脏成纤维细胞中的内质网应激（ER）体外，并在带有MI和恢复的小鼠中 高血压心脏中的磷酸化。 ER应力的激活不利于内皮，心脏 成纤维细胞和心肌细胞。这些发现树立了这项工作的科学前提，提供了基础 AC-SDKP代表现有心脏药物疗法的有益补充。我们的中心 假设是，AC-SDKP通过 抑制ER应力。我们建议使用高血压或LAD引起的心力衰竭的小鼠模型 解决以下两个目标：（（ 1） 我们将确定AC-SDKP是否保护心脏并提供 具有MI或高血压的小鼠中ARB，ACEI或eplerenone对ARB，ACEI或eplerenone的其他额外的心脏保护作用（（（ 2） 还有我们 将证明AC-SDKP通过抑制高血压或LAD来改善小鼠的心脏功能 通过PI3K/AKT途径有害的ER应力。许多条件和组织特异性敲除女性 雄性老鼠将被雇用。为该项目招募了一支拥有重要专家的团队，这将适用 最新的体内，细胞和分子技术的结合，包括心脏的测量 超声心动图的重塑和功能在非麻醉小鼠和radiotelemetry中，可以检测到 血压，心电图和意识小鼠的心率。这些研究将有助于定义 AC-SDKP和HF之间的原因效应及其与HF保护的机制之间的关系。

项目成果

Knockout of ACE-N facilitates improved cardiac function after myocardial infarction.

ACE-N 的敲除有助于改善心肌梗塞后的心脏功能。

• DOI: 10.1016/j.jmccpl.2022.100024
• 发表时间: 2023
• 期刊: Journal of molecular and cellular cardiology plus
• 作者: Suhail,Hamid;Peng,Hongmei;Xu,Jiang;Sabbah,HaniN;Matrougui,Khalid;Liao,Tang-Dong;Ortiz,PabloA;Bernstein,KennethE;Rhaleb,Nour-Eddine
• 通讯作者: Rhaleb,Nour-Eddine

Role of Kinins in Hypertension and Heart Failure.

• DOI: 10.3390/ph13110347
• 发表时间: 2020-10-28
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Hamid S;Rhaleb IA;Kassem KM;Rhaleb NE
• 通讯作者: Rhaleb NE