Investigating Mixed Lineage Kinase 3 as a blood pressure-independent protein kinase G1 effector in heart failure

研究混合谱系激酶 3 作为心力衰竭中血压独立的蛋白激酶 G1 效应子

基本信息

批准号：
10418579
负责人：
Robert Morris Blanton
金额：
$ 71.88万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418579
关键词：
Abnormal Cell Acute Affect Blood Pressure Blood Vessels Cardiac Myocytes Cells Chronic Clinical Cyclic GMP-Dependent Protein Kinases Diagnosis Drops EFRAC Echocardiography Fibrosis Financial compensation Genetic Heart Heart failure Human Hypertension Hypertrophy Hypotension Hypotensives Impairment In Vitro Knowledge Lead Left Left Ventricular Dysfunction Left Ventricular Ejection Fraction Left Ventricular Function Left Ventricular Hypertrophy Left Ventricular Remodeling Left ventricular structure Luciferases Measures Mediating Medicine Modeling Molecular Mus Myocardial Myocardial Infarction Myocardium Nature Nitrates Pathologic Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Physiologic intraventricular pressure Physiologic pulse Protein Kinase Proteins Regulation Relaxation Role Signal Transduction Signaling Protein Smooth Muscle Myocytes Stress Syndrome Tamoxifen Telemetry Testing Therapeutic Effect Tissues Transgenes Transgenic Organisms Treatment Failure Vascular Smooth Muscle Vasodilation Ventricular Ventricular Remodeling arterial stiffness blood pressure reduction blood pressure regulation constriction heart preservation hemodynamics improved improved outcome in vivo inhibitor kinase inhibitor loss of function mixed lineage kinase 3 mortality muscle strength novel novel therapeutic intervention novel therapeutics preclinical study pressure programs response sildenafil therapeutic candidate treatment strategy valsartan

项目摘要

The cGMP-dependent protein kinase 1 alpha (PKG1α) opposes pathological left ventricular (LV) hypertrophy and remodeling via roles in the cardiac myocyte (CM) and regulates blood pressure by promoting vascular smooth muscle cell (VSMC) relaxation and vasodilation. Drugs which activate PKG1, including nitrates, sacubitril/valsartan, vericiguat, and others have improved mortality in heart failure with reduced LV ejection fraction (HFrEF) and thus represent a central advance in HFrEF treatment. However, these therapies remain limited by incomplete efficacy in HFrEF. Furthermore, hypotension from PKG1-induced vasodilation has severely limited the practical use of these agents. The overarching hypothesis of this program is that identifying downstream PKG1α anti-remodeling substrates in the LV can reveal novel therapeutic candidates to overcome these critical limitations of current PKG1-activating drugs. We have identified Mixed Lineage Kinase 3 (MLK3) as a novel PKG1α-interacting protein and anti-remodeling molecule. We propose to explore the following exciting findings which identify MLK3 as a translationally relevant molecule in HFrEF. 1) PKG1α-MLK3 interaction declines in the failing LV, and MLK3 is required for PKG1α-mediated therapeutic effects of sildenafil on LV function after pressure overload, thus identifying disruption of myocardial MLK3 regulation by PKG as promoting LV remodeling and decreasing the efficacy of PKG1-activating drugs in HF. 2) MLK3 kinase function opposes pathological CM and LV dysfunction and remodeling but does not affect blood pressure in vivo. 3) MLK3 deletion promotes hypertension in vivo, but MLK3 regulation of blood pressure occurs through MLK3 kinase independent mechanisms and independently of signaling by PKG1α. We propose to test a two-part novel model in which 1) PKG1α activation of MLK3 promotes LV compensation to pressure overload through MLK3 kinase-dependent mechanisms in the CM; and 2) MLK3 opposes hypertension through kinase-independent effects on vascular stiffness through a role in the VSMC. SA1 will use novel MLK3 cell-specific deletion models developed in our lab to determine the CM and SMC-specific roles of MLK3 in basal regulation of LV function and blood pressure and in the chronic LV response to pressure overload or myocardial infarction. SA2 will determine the kinase dependent versus kinase independent effects of MLK3 on LV function and blood pressure. SA3 will determine the translational relevance of MLK3 to HF treatment by testing the requirement of MLK3 for LV therapeutic effects versus blood pressure effects of currently available PKG1-activating drugs. These studies will define novel mechanisms through which MLK3 regulates blood pressure and through which MLK3 blood pressure- independent functions mediate the therapeutic effect of current PKG1-activating drugs. These studies have the potential to identify MLK3 kinase activation as a novel therapeutic strategy to promote PKG1 therapeutic effects on LV function and remodeling but avoid undesired hypotension which has limited PKG1 activating drugs.

cGMP 依赖性蛋白激酶 1 α (PKG1α) 对抗病理性左心室 (LV) 肥大通过在心肌细胞 (CM) 中的作用进行重塑，并通过促进血管生成来调节血压激活 PKG1 的药物，包括硝酸盐、平滑肌细胞 (VSMC) 松弛和血管舒张。沙库巴曲/缬沙坦、维西呱等药物通过降低左心室射血量降低了心力衰竭的死亡率分数（HFrEF），因此代表了 HFrEF 治疗的主要进展。然而，这些疗法仍然存在。此外，PKG1 诱导的血管舒张导致的低血压也很严重。限制了这些药物的实际使用。该计划的首要假设是识别。左室下游 PKG1α 抗重塑底物可以揭示新的治疗候选物以克服目前 PKG1 激活药物的这些关键局限性我们已经确定了混合谱系激酶 3 (MLK3)。作为一种新型 PKG1α 相互作用蛋白和抗重塑分子，我们建议探索以下令人兴奋的内容。研究结果表明 MLK3 是 HFrEF 中的翻译相关分子 1) PKG1α-MLK3 相互作用。衰竭 LV 下降，并且 MLK3 是 PKG1α 介导的西地那非对 LV 治疗作用所必需的压力超负荷后的功能，从而确定 PKG 对心肌 MLK3 调节的破坏促进左心室重塑和 PKG1 激活药物在心力衰竭中的疗效降低 2) MLK3 激酶功能相反。病理性 CM 和 LV 功能障碍和重塑但不影响体内血压 3) MLK3 缺失。促进体内高血压，但 MLK3 对血压的调节是通过不依赖 MLK3 激酶的方式进行的我们建议测试一个由两部分组成的新模型，其中 1) MLK3 的 PKG1α 激活通过 MLK3 激酶依赖性促进左心室对压力超负荷的补偿 CM 中的机制；2) MLK3 通过对血管的激酶独立作用来对抗高血压 SA1 中的作用将使用我们实验室开发的新型 MLK3 细胞特异性缺失模型。确定 MLK3 在 LV 功能和血压基础调节中的 CM 和 SMC 特异性作用， SA2 将决定左心室对压力超负荷或心肌梗塞的慢性反应。 MLK3 对 LV 功能和血压的依赖性与激酶依赖性将决定。通过测试 MLK3 对 LV 治疗效果的要求来确定 MLK3 与 HF 治疗的转化相关性这些研究将确定新的 PKG1 激活药物对血压的影响。 MLK3 调节血压的机制以及 MLK3 血压- 这些研究表明，当前 PKG1 激活药物的治疗效果具有独立的功能。确定 MLK3 激酶激活作为促进 PKG1 治疗效果的新型治疗策略的潜力左心室功能和重塑，但避免不良低血压，这限制了 PKG1 激活药物。