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

基本信息

  • 批准号:
    10336561
  • 负责人:
  • 金额:
    $ 47.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
在美国,高血压是一个主要的卫生保健负担,影响三分之一的成年人。高血压是 与伴随的冠状动脉疾病伴心肌梗死(MI)和心力衰竭(HF)相关。在 本研究将定义N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸(Ac-SDKP)如何保护心脏结构, 在两种模型[血管紧张素II(Ang II)高血压-或 永久性左冠状动脉前降支结扎(LAD)]。我们和其他人报道,血管紧张素II诱导的 高血压或LAD导致与心脏结构重构和功能受损相关的HF。AC- SDKP是由胸腺素β 4(Thymosin β 4,T β 4)通过两种酶(meprin β 4和脯氨酰寡肽酶)连续产生的 (POP).循环和组织Ac-SDKP取决于血管紧张素转换酶(ACE)活性,因为Ac-SDKP是一种血管紧张素转换酶。 SDKP主要被ACE的N-末端活性侧(ACE-N)降解。ACEi是治疗HF的一线药物。 ACEi具有强烈的副作用,如低血压、咳嗽、皮疹、血管神经性水肿、高钾血症, 味觉障碍,而Ac-SDKP没有,即使在高剂量(高达48 mg/kg/d)。此外,Ac-SDKP也下降了- 在狗和慢性HF患者的心肌中调节。Ac-SDKP治疗是否以及如何 抢救高血压或LAD引起的心脏并发症仍有待阐明。增加循环AC- SDKP不仅能抑制纤维化和炎症细胞介质向损伤心肌的浸润, 还改善了患有LAD或高血压的小鼠的心脏功能(初步数据)。我们发现,AC- SDKP抑制体外心脏成纤维细胞和MI小鼠的内质网(ER)应激, 高血压心脏中磷酸化AKT。ER应激的激活对内皮细胞、心脏细胞和心肌细胞都是有害的。 成纤维细胞和心肌细胞。这些发现为这项工作奠定了科学前提,为研究提供了基础。 Ac-SDKP是对现有心脏药物治疗的有益补充。我们的中央 假设Ac-SDKP通过以下途径保护和加强心脏保护以对抗心力衰竭: 抑制ER应激。我们建议使用高血压或LAD诱导的心力衰竭小鼠模型 以达致以下两个目标:( 第一章 我们将确定Ac-SDKP是否能保护心脏, ARB、ACEi或依普利酮对MI或高血压小鼠的额外心脏保护作用,( (二) 我们 将证明Ac-SDKP通过抑制高血压或LAD小鼠的心功能, 通过PI 3 K/AKT途径抑制有害的ER应激。一些条件性和组织特异性敲除的雌性 并使用雄性小鼠。为该项目招募了一个具有重要专业知识的团队,该团队将采用 最先进的体内、细胞和分子技术的组合,包括心脏的测量, 在非麻醉小鼠中通过超声心动图和无线电遥测, 清醒小鼠的血压、心电图和心率。这些研究将有助于确定 Ac-SDKP与HF的因果关系及其对HF的保护作用机制。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 影响因子:
    0
  • 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:
  • 影响因子:
    0
  • 作者:
    Hamid S;Rhaleb IA;Kassem KM;Rhaleb NE
  • 通讯作者:
    Rhaleb NE
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NOUR-EDDINE RHALEB其他文献

NOUR-EDDINE RHALEB的其他文献

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{{ truncateString('NOUR-EDDINE RHALEB', 18)}}的其他基金

Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    7319008
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    6831679
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    7656903
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    6558190
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    6693301
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    7483249
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    7904241
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:
Hypertension and Collagen: Effect of Ac-SDKP
高血压和胶原蛋白:Ac-SDKP 的作用
  • 批准号:
    6989064
  • 财政年份:
    2003
  • 资助金额:
    $ 47.45万
  • 项目类别:

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