Mechanisms Underlying Vascular Aging

血管老化的机制

• 批准号: 10063951
• 负责人: JAMES Kuang-Jan LIAO
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-22 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063951
• 关键词: Actins; Affect; Age; Aging; Aorta; Atherosclerosis; Attenuated; Biomechanics; Blood Vessels; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronology; Collagen; Collagen Fiber; Cyclic AMP-Dependent Protein Kinases; Deposition; Development; Down-Regulation; Elastin; Elastin Fiber; Elderly; Elongation Factor; Extracellular Matrix; Human; Hybrids; Laboratories; Lead; Mechanics; Mediating; Microvascular Dysfunction; Morphology; Mus; Mutant Strains Mice; Mutation; Obesity; Pathogenesis; Pathologic; Pharmacology; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiologic pulse; Physiological; Pilot Projects; Play; Population; Process; Procollagen; Property; Protein Isoforms; Protein-Serine-Threonine Kinases; ROCK1 gene; Research; Rho-associated kinase; Risk Factors; Role; Serum Response Factor; Signal Pathway; Smoking; Smooth Muscle Myocytes; Structure; Systemic hypertension; Testing; Thick; Tissues; Vascular Diseases; Vascular Smooth Muscle; Vasomotor; Yeasts; age related; arterial stiffness; cardiovascular disorder risk; cardiovascular risk factor; cell type; comorbidity; connective tissue growth factor; endothelial dysfunction; fasudil; gain of function; genetic approach; hemodynamics; improved; in vivo; inhibitor/antagonist; loss of function; mechanical properties; mutant; neointima formation; non-compliance; rho; systolic hypertension

Vascular disease increases with advancing age and is the leading cause of death in the elderly population. The most prominent feature of vascular aging with respect to the cardiovascular system is the gradual and progressive stiffening of the vessel wall. Indeed, age-related aortic stiffness can occur in the absence of any cardiovascular risk factors, and antedates the development of systolic hypertension and cardiovascular disease. Thus, the aging process itself is an important risk factor for vascular stiffness. The pathogenesis of age-related vascular stiffening is marked by non-compliance of the vessel wall due to loss or fragmentation of elastin fibers, deposition of non-compliant collagen fibers, endothelial dysfunction, and increased vascular tone. This leads to progressive microvascular dysfunction and the development of systemic hypertension. Signaling pathways, which affect the compliance and contractility of the vessel wall, therefore, may be important contributors to the pathogenesis of vascular aging or stiffening. Because SMCs are the predominant cell type in the vessel wall of conduit arteries that stiffens with age, abnormal SMC function will probably play a central role in mediating the mechanical and morphological properties of vascular aging. Indeed, physiological and pathological studies suggest that SMC phenotype and function are critical determinants of both passive and active biomechanical properties of the vessel wall. Accordingly, we will focus on the role of ROCK in SMC and determine whether SMC ROCKs are necessary and/or sufficient in mediating arterial stiffening, and if so, to determine the relevant mechanisms involved. Specific aim 1 will investigate the SMC-specific effects of ROCKs on vascular aging. The hypothesis to be tested is that ROCKs are necessary and sufficient in mediating age-related vascular stiffening. For loss- of-function studies, we will generate SMC-specific ROCK1–/– and ROCK2–/– mice (smROCK1–/– and smROCK2–/–) using smSMC-CreERT2 mice and conditional ROCK1/2flox/flox mice. For gain-of-function studies, we will generate SMC-specific caROCK mice using smSMC-CreERT2 mice and conditional caROCKflox/flox mice. In addition, we will determine whether co-morbidities of advancing age in humans such as obesity and/or atherosclerosis can activate SMC ROCK to accelerate the vascular aging. Specific aim 2 will investigate the role of eEF1A and SRF phosphorylation in mediating the downstream effects of ROCKs on vascular aging. The hypothesis to be tested is that phosphorylation of eEF1A and SRF by ROCK mediates both contractile and non-contractile SMC functions that contribute to vascular aging. Specifically, we will 1) determine whether SMC eEF1A and SRF phosphorylation increases with age, 2) develop phosphor-mutant eEF1A and SRF mice, and 3) determine whether eEF1A and SRF phosphorylation contributes to ROCK-mediated vascular changes that are associated with aortic stiffening.

血管疾病随着年龄的增长而增加，是老年人死亡的主要原因 人口相对于心血管系统，血管老化的最突出特征是 血管壁逐渐变硬。事实上，年龄相关的主动脉僵硬可以发生在 没有任何心血管危险因素，并且早于收缩期高血压的发展， 心血管疾病因此，衰老过程本身是血管僵硬的重要风险因素。的 与年龄相关的血管硬化的发病机制以血管壁的不顺应性为标志， 弹性蛋白纤维的断裂、非顺应性胶原纤维的沉积、内皮功能障碍，以及 血管张力增加。这导致进行性微血管功能障碍和全身性 高血压因此，影响血管壁顺应性和收缩性的信号通路， 可能是血管老化或硬化的发病机制的重要因素。因为SMC是 血管壁中的主要细胞类型随着年龄的增长而变硬，异常的SMC功能将 可能在介导血管老化的机械和形态学特性中发挥核心作用。 事实上，生理和病理研究表明，SMC的表型和功能是至关重要的 血管壁的被动和主动生物力学特性的决定因素。因此，我们将重点 ROCK在SMC中的作用，并确定SMC ROCK是否是必要的和/或足够的介导 动脉硬化，如果是这样，以确定相关的机制。 具体目标1将研究ROCK对血管老化的SMC特异性作用。的假设 ROCK在介导年龄相关性血管硬化中是必要和充分的。对于损失- 在功能研究中，我们将产生SMC特异性ROCK 1-/-和ROCK 2-/-小鼠（smROCK 1-/-和 smROCK2-/-）。对于功能获得性研究， 我们将使用smSMC-CreERT 2小鼠和条件性caROCKflox/flox小鼠产生SMC特异性caROCK小鼠。 此外，我们将确定人类年龄增长的共病，如肥胖和/或 动脉粥样硬化可激活SMC ROCK，加速血管老化。 具体目标2将研究eEF 1A和SRF磷酸化在介导细胞凋亡中的作用。 ROCKs对血管老化的下游影响。有待检验的假设是， ROCK介导的eEF 1A和SRF介导收缩和非收缩SMC功能， 血管老化。具体来说，我们将1）确定SMC eEF 1A和SRF磷酸化是否增加 2）开发磷酸化突变的eEF 1A和SRF小鼠，和3）确定eEF 1A和SRF是否 磷酸化导致ROCK介导的血管变化，其与主动脉硬化相关。

项目成果

SALAD-BAAR: A numerical risk score for hospital admission or emergency department presentation in ambulatory patients with cardiovascular disease.

• DOI: 10.1002/clc.23525
• 发表时间: 2021-03
• 期刊: Clinical cardiology
• 影响因子: 2.7
• 作者: Anyanwu EC;Chua RFM;Besser SA;Sun D;Liao JK;Tabit CE
• 通讯作者: Tabit CE

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.

• DOI: 10.1016/j.jacbts.2022.07.001
• 发表时间: 2023-01
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Liu, Pang -Yen;Fukuma, Nobuaki;Hiroi, Yukio;Kunita, Akiko;Tokiwa, Hiroyuki;Ueda, Kazutaka;Kariya, Taro;Numata, Genri;Adachi, Yusuke;Tajima, Miyu;Toyoda, Masayuki;Li, Yuxin;Noma, Kensuke;Harada, Mutsuo;Toko, Haruhiro;Ushiku, Tetsuo;Kanai, Yoshimitsu;Takimoto, Eiki;Liao, James K.;Komuro, Issei
• 通讯作者: Komuro, Issei

Community Health Workers Reduce Rehospitalizations and Emergency Department Visits for Low-Socioeconomic Urban Patients With Heart Failure.

社区卫生工作者减少了对患有心力衰竭的低社会经济城市患者的重新住院和急诊科的访问。

• DOI: 10.1097/hpc.0000000000000220
• 发表时间: 2020-09
• 期刊: Critical pathways in cardiology
• 作者: Vohra AS;Chua RFM;Besser SA;Alcain CF;Basnet S;Battle B;Coplan MJ;Liao JK;Tabit CE
• 通讯作者: Tabit CE

Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening.

• DOI: 10.1080/14728222.2020.1712593
• 发表时间: 2020-01
• 期刊: Expert opinion on therapeutic targets
• 影响因子: 5.8
• 作者: Yu B;Sladojevic N;Blair JE;Liao JK
• 通讯作者: Liao JK

A practical treatment for COVID-19 and the next pandemic.

• DOI: 10.1002/prp2.988
• 发表时间: 2022-08
• 期刊: PHARMACOLOGY RESEARCH & PERSPECTIVES
• 影响因子: 2.6
• 作者: Bhattacharya, Jahar;Booy, Robert;Casadevall, Arturo;Dela Cruz, Charles;Fedson, David S.;Garcia, Joe G. N.;Grohmann, Gary;Hung, Ivan F. N.;Jacobson, Jeffrey R.;Jennings, Lance C.;Kobzik, Lester;Leligdowicz, Aleksandra;Liao, James K.;Martin, Jennifer H.;Musher, Daniel M.;Serhan, Charles N.;Tashiro, Masato
• 通讯作者: Tashiro, Masato