Adenosine Transport in the Aged Heart

老年心脏中的腺苷运输

• 批准号: 7470844
• 负责人: RICHARD ALLAN FENTON
• 金额: $ 6.66万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470844
• 关键词: ATP sensitive potassium channel complex; Adenosine; Adenosine Kinase; Adenylate Cyclase; Adrenergic Agents; Adrenergic Receptor; Age; Aging; Animals; Apoptosis; Appearance; Attenuated; Binding; Cardiac Myocytes; Cell physiology; Cell surface; Cells; Cellular Membrane; Condition; Cyclic AMP-Dependent Protein Kinases; Depressed mood; Development; Disruption; Feedback; Glucose; Glycolysis; Goals; Heart; Impairment; Left; Membrane; Messenger RNA; Metabolic; Movement; Muscle Cells; Myocardium; Nucleotides; Phorbol; Phorbols; Phosphoric Monoester Hydrolases; Phosphorylation; Process; Production; Protein Kinase; Protein Kinase C; Proteins; Public Health; Purinergic P1 Receptors; Purines; Role; Ventricular; adenosine transporter; adenylate kinase; adrenergic; aged; base; design; glucose transport; heart function; interstitial; neurotransmitter release; oxidation; preconditioning; purine; receptor; research study; response; uptake; young adult

DESCRIPTION (provided by applicant): Adenosine impacts heart function and survival under normal and pathological conditions by interacting at the cell surface with adenosine receptor subtypes A1, A2 and A3, and modulating glucose transport, glycolysis, glucose oxidation, neurotransmitter release and contractility. Adenosine is also a negative feedback regulator of 2-adrenergic stimulation, thereby protecting the heart from the lethal consequences of adrenergic overdrive. By modulating protein kinase C (PKC?) and phosphatase activities, adenosine modulates processes that require substrate phosphorylation for activation, such as preconditioning and apoptosis. As a substrate for adenosine kinase, adenosine is also vital precursor of the cardiomyocyte nucleotide pool. The resulting AMP modulates the activity of AMP Kinase, a vital regulator of the cellular metabolic state, prior to further phosphorylation to ADP and ATP. Adenosine enters and leaves the cell via specific concentrative and equilibrative transporters. In that the transport of adenosine across the cellular membrane is a focal point around which revolve many scenarios that critically impact the function of the heart, disruption of adenosine transport can be detrimental to heart survival. In the aged heart, evidence has been found suggesting animal impairment of adenosine transport. It is hypothesized that in the aged ventricular myocardium, the adenosine concentrative and equilibrative transporter activities are reduced. The goal of this study is to verify this hypothesis enabling further study of mechanisms by which aging alters adenosine transport mechanisms. This hypothesis will be studied by considering the following SPECIFIC AIMS: Specific Aim 1: Determine if the appearance of intracellular free adenosine in the aged heart rises to a greater level than in the young adult heart when cellular adenosine production is enhanced. Specific Aim 2: Determine if the protein and mRNA levels of adenosine transporters are depressed in the aged heart. Specific Aim 3: Determine if the adenosine transporters are phosphorylated by PKC in the adenosine- or phorbol-stimulated heart and if the level of phosphorylation attained is depressed in the aged vs young adult heart. These studies will further the development of additional hypotheses designed to gain a better understanding of how aging alters heart function. PUBLIC HEALTH RELEVANCE Adenosine is a naturally produced metabolite that is important to the normal metabolic, contractile and electrical function of the heart. Adenosine transporters located in cardiomyocyte membranes control the movement of adenosine into and out of the cell, thus influencing the many aspects of cellular function modulated by adenosine. In the aged heart transporter function appears to be attenuated. This study proposes experiments exploring the basis for the impaired transporter function.

描述（由申请人提供）：腺苷通过在细胞表面与腺苷受体亚型 A1、A2 和 A3 相互作用，并调节葡萄糖转运、糖酵解、葡萄糖氧化、神经递质释放和收缩性，影响正常和病理条件下的心脏功能和存活。腺苷还是 2-肾上腺素能刺激的负反馈调节剂，从而保护心脏免受肾上腺素能过度驱动的致命后果。通过调节蛋白激酶 C (PKC?) 和磷酸酶活性，腺苷调节需要底物磷酸化才能激活的过程，例如预处理和细胞凋亡。作为腺苷激酶的底物，腺苷也是心肌细胞核苷酸库的重要前体。产生的 AMP 在进一步磷酸化为 ADP 和 ATP 之前调节 AMP 激酶（细胞代谢状态的重要调节剂）的活性。腺苷通过特定的集中和平衡转运蛋白进入和离开细胞。由于腺苷跨细胞膜的运输是一个焦点，许多严重影响心脏功能的情况都围绕着这个焦点，腺苷运输的破坏可能不利于心脏的存活。在衰老的心脏中，有证据表明动物的腺苷运输受损。据推测，在老化的心室心肌中，腺苷浓度和平衡转运蛋白活性降低。本研究的目的是验证这一假设，以便进一步研究衰老改变腺苷转运机制的机制。将通过考虑以下具体目标来研究该假设： 具体目标 1：确定当细胞腺苷产生增强时，老年心脏中细胞内游离腺苷的出现是否比年轻成人心脏中上升到更高水平。具体目标 2：确定老年心脏中腺苷转运蛋白和 mRNA 水平是否下降。具体目标 3：确定腺苷转运蛋白是否在腺苷或佛波醇刺激的心脏中被 PKC 磷酸化，以及在老年人心脏中与年轻人心脏中所达到的磷酸化水平是否降低。这些研究将进一步发展其他假设，旨在更好地了解衰老如何改变心脏功能。 公共卫生相关性 腺苷是一种天然产生的代谢物，对心脏的正常代谢、收缩和电功能很重要。位于心肌细胞膜中的腺苷转运蛋白控制腺苷进出细胞的运动，从而影响腺苷调节的细胞功能的许多方面。在老年人中，心脏转运蛋白的功能似乎减弱。这项研究提出了探索转运蛋白功能受损的基础的实验。