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A novel treatment of aortic disease in Marfan Syndrome targeting oxidative stress and PKG dysregulation

针对氧化应激和 PKG 失调的马凡综合征主动脉疾病的新疗法

基本信息

批准号：
10588164
负责人：
RENATE B PILZ
金额：
$ 73.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588164
关键词：
Acute Adhesions Adrenergic Agents Adrenergic Antagonists Adrenergic beta-Antagonists Affect Age Alleles Aneurysm Antioxidants Aorta Aortic Aneurysm Aortic Diseases Aortic Rupture Apoptosis Attenuated Cardiovascular Abnormalities Cell physiology Cells Cessation of life Chest Collagen Complement Cyclic GMP Cyclic GMP-Dependent Protein Kinases DNA Data Deposition Development Diameter Disease Dissection Dose Drug Metabolic Detoxication Elastic Fiber Elastin Enzymes Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Eye Abnormalities FBN1 Fibrosis Functional disorder Gene Expression Gene Expression Profile Generations Genetic Diseases Goals Grant Histology Human Human Milk Impairment In Vitro Inherited Knock-out Legal patent Life Lipids LoxP-flanked allele Maintenance Marfan Syndrome Matrix Metalloproteinases Mechanical Stress Medial Microfibrils Mitochondria Mus Mutation Nitric Oxide Nitric Oxide Synthase Oral Oxidative Stress Pathology Pathway interactions Patients Peroxonitrite Persons Phenotype Play Prevalence Production Proliferating Propranolol Protein Isoforms Proteins Reactive Inhibition Reactive Nitrogen Species Reactive Oxygen Species Reporting Role Schedule Signal Transduction Smooth Muscle Myocytes Source Superoxide Dismutase Superoxides Tamoxifen Testing Thoracic Aortic Aneurysm Time Transgenes Up-Regulation Vitamin B 12 age related analog ascending aorta autosome catalase cobinamide drinking water extracellular fibrillin gain of function mutation improved in vivo induced pluripotent stem cell inhibitor knock-down loss of function mutation mimetics mouse model mutant nitrosative stress novel overexpression oxidation pharmacologic postnatal premature prevent public health relevance repaired skeletal abnormality small hairpin RNA stress activated protein kinase stress kinase treatment strategy

项目摘要

Summary Aortic aneurysms and dissections are the most serious and deadly manifestations of Marfan Syndrome (MFS), and current therapies to prevent aortic dilation are only moderately effective. MFS is caused by mutations or deletions in fibrillin-1 (Fbn1), a component of extracellular microfibrils, which surround and connect elastic fibers to smooth muscle cells (SMCs) in the aortic media. Reduced fibrillin function alters signaling between extracellular matrix and SMCs, resulting in SMC apopotosis and extracellular matrix degradation. In addition, the altered signaling leads to increased production of reactive oxygen species (ROS) and nitric oxide (NO), increasing oxidative and nitrosative stress and activating protein kinase G (PKG) via the NO/cGMP pathway. Although the increased ROS, reactive nitrogen species (RNS), and PKG activation contribute to aneurysm formation in MFS, neither the sources of ROS/RNS nor the effects of oxidative/nitrosative stress on SMC functions are fully understood. The vitamin B12 analog cobinamide, on which we hold several patents, is a strong and versatile antioxidant that can neutralize ROS and RNS, including NO. During the last grant period, we showed that mice with an activating PKG1 mutation (Prkg1R177Q) that causes thoracic aneurysms and dissections in humans, develop aortic dilation associated with increased oxidative stress and media degeneration⸺elastic fiber fragmentation, increased matrix metalloproteinase activity, media fibrosis, and SMC apoptosis; cobinamide treatment completely prevented these changes. Preliminary data show that cobinamide also reduces aortic dilation and prevents elastic fiber fragmentation and SMC apoptosis in a mouse model of MFS (Fbn1C1041G/+), while reducing markers of oxidative stress and excess PKG signaling. We hypothesize that increased ROS/RNS combined with PKG activation from increased NO synthase (NOS2) drive abnormal SMC functions and aortic pathology in MFS, and that an optimized dose schedule of cobinamide will prevent aortic dilation and improve survival in mice with MFS, especially when combined with a -blocker. In Aim 1, we will determine the mecha- nisms and consequences of excess ROS/RNS generation in human fibrillin1-deficient or mutant (iPSC-derived) SMCs, using shRNA knockdown and pharmacological approaches to inhibit ROS/RNS-generating enzymes and PKG in vitro. We will assess contributions of excess NO synthase and PKG activity to the progression of aortic disease in vivo, by inducing SMC-specific knockout of NOS2 or PKG1 in Fbn1C1041G/+ mice. We will also test whether ROS detoxification by SMC-specific catalase overexpression ameliorates aortic pathology. In Aim2, we will determine the optimal cobinamide dose and starting time to prevent aortic dilation and death from aortic dissections in mice with moderate (Fbn1C1041G/+) and severe (Fbn1mgR/mgR) MFS, respectively. In addition, we will combine cobinamide with the β-blocker propranolol, because cobinamide prevents aortic media degeneration, while propranolol reduces mechanical stress without affecting degenerative changes in the media. These studies could lead to considerably improved treatment of the aortic disease in patients with MFS.

总结