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

在美国，高血压是一个主要的医疗负担，每3个成年人中就有1人受到影响。高血压是 伴有冠状动脉疾病，并伴有心肌梗死(MI)和心力衰竭(HF)。在……里面 在这项研究中，我们将确定N-乙酰-丝氨酸-天冬氨酰-赖氨酰-脯氨酸(Ac-SDKP)如何保护心脏结构和 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术(LAD)]。我们和其他人报告了Ang II诱导的 高血压或左前降支导致心力衰竭，并伴有心脏结构重构和功能受损。AC- 胸腺肽4(T4)在两种酶的作用下相继产生SDKP，即Meprin和Pro基寡肽酶 (流行音乐)。循环和组织中的Ac-SDKP依赖于血管紧张素转换酶(ACE)的活性，因为Ac-SDKP- SDKP主要由ACE的N末端活性侧(ACE-N)降解。ACEI是治疗心力衰竭的一线药物。 血管紧张素转换酶抑制剂有很强的副作用，如低血压、咳嗽、皮疹、血管神经性水肿、高钾血症和 Ac-SDKP没有，即使在高剂量(高达48 mg/kg/d)时也没有。另外，ac-sdkp出现故障- 在犬和慢性心力衰竭患者的心肌中进行调节。AC-SDKP疗法是否以及如何能够 抢救性高血压或左前降支引起的心脏并发症仍有待阐明。增加循环交流- SDKP不仅能抑制损伤心肌的纤维化和炎性细胞浸润的介质，而且 也改善了患有LAD或高血压的小鼠的心功能(初步数据)。我们发现了Ac- SDKP抑制心肌成纤维细胞内质网应激的实验研究 高血压心脏中的磷酸化AKT。内质网应激的激活对血管内皮细胞、心脏 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 Ac-SDKP是对现有心脏药物治疗的有益补充。我们的中央 假说认为ac-SDKP可保护和加强心脏对心力衰竭的保护作用 抑制内质网应激。我们建议使用高血压或LAD所致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是否保护心脏和提供 ARB、ACEI或依普利酮对心肌梗死或高血压小鼠的额外心脏保护作用( 2) 而我们 将证明ac-SDKP通过抑制高血压或LAD小鼠的心脏功能而改善其心功能。 通过PI3K/AKT途径产生有害的内质网应激。一些有条件的和组织特异性的基因敲除雌性 雄性老鼠将被雇佣。为这个项目招募了一个具有重要专业知识的团队，这将适用于 结合最先进的活体、细胞和分子技术，包括心脏测量 应用超声心动图和放射性遥测技术检测非麻醉小鼠心脏重构和功能 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的保护机制。

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.