Adenosine Transport in the Aged Heart

老年心脏中的腺苷运输

• 批准号: 7586834
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586834
• 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; Cyclic AMP-Dependent Protein Kinases; Development; 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; Purinergic P1 Receptors; Purines; Role; Ventricular; adenosine transporter; adenylate kinase; adrenergic; aged; base; depressed; design; glucose transport; heart function; interstitial; neurotransmitter release; oxidation; preconditioning; public health relevance; 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）：腺苷通过与腺苷受体亚型A1，A2和A3在正常和病理条件下在正常和病理条件下影响心脏功能和存活，并调节葡萄糖转运，糖酵解，葡萄糖氧化，Neurototransmitter释放和降低性。腺苷也是2-肾上腺素刺激的负反馈调节剂，从而保护心脏免受肾上腺素能超速驱动的致命后果。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以进行激活的过程，例如预处理和凋亡。作为腺苷激酶的底物，腺苷也是心肌细胞核苷酸池的重要前体。所得的AMP调节AMP激酶的活性，AMP激酶是细胞代谢状态的重要调节剂，然后在进一步磷酸化ADP和ATP之前。腺苷通过特异性浓度和平衡转运蛋白进入并离开细胞。因为腺苷在整个细胞膜上的运输是一个焦点，围绕着许多纵向影响心脏功能的许多情况，因此腺苷转运的破坏可能对心脏存活有害。在老年人的心脏中，发现有证据表明腺苷转运的动物损害。假设在老化的心室心肌，腺苷浓度和平衡转运蛋白活性降低。这项研究的目的是验证这一假设，以进一步研究衰老会改变腺苷转运机制的机制。通过考虑以下特定目的来研究该假设：具体目的1：确定老年心脏中细胞内游离腺苷的出现是否比在增强细胞腺苷的产生时更大的水平上升到更大的水平。具体目标2：确定腺苷转运蛋白的蛋白质和mRNA水平是否在老年心脏中抑郁。具体目标3：确定腺苷转运蛋白是否在腺苷或佛波尔刺激的心脏中被PKC磷酸化，以及在老年人与年轻的成人心脏中达到的磷酸化水平是否降低。这些研究将进一步发展旨在更好地了解衰老如何改变心脏功能的其他假设。 公共卫生相关性腺苷是一种天然产生的代谢产物，对心脏的正常代谢，收缩和电气功能很重要。位于心肌细胞膜中的腺苷转运蛋白控制腺苷进入和流出细胞的运动，从而影响腺苷调节的细胞功能的许多方面。在老化的心脏转运蛋白功能中，似乎已减弱。这项研究提出了探索转运蛋白功能受损的基础的实验。