Calcineurin's role in circadian regulation of cardiac function and remodeling

研究综述 昼夜节律是自我维持的，在分子，生物化学和行为方面的24小时周期 帮助生物体为预期的生理需求变化做好准备的参数。许多 重要的心血管因素，包括新陈代谢、心率、血压和激素 释放，在24小时内振荡。在人类中，不良心脏事件的发生率，如 心肌梗死、室性心动过速和缺血性心脏病死亡，根据不同的 一天中的时间和昼夜节律的被迫变化与心脏病风险增加有关。 失败心血管疾病是美国的主要死亡原因，其发病率是 达到了全球流行的程度。尽管有压倒性的证据表明 心血管健康的昼夜节律，很少有人知道关于昼夜节律调节 控制心脏功能和重塑的细胞内信号通路。我们最近发现 钙激活蛋白磷酸酶活性的大昼夜振荡的证据 正常健康心脏中的钙调神经磷酸酶这一发现是值得注意的，因为钙调神经磷酸酶的激活 主要被认为是一种导致心脏肥大和衰竭的病理过程。我们 假设钙调神经磷酸酶活性每日波动与其他神经元形成相互依赖的反馈回路， 细胞过程有助于协调心脏功能和重塑的变化， 生理需求的变化。此外，我们假设，正常的时间中断， 钙调神经磷酸酶活性增加心脏应激并导致心脏功能恶化的关系 功能这项资助的目标是确定钙调神经磷酸酶活性昼夜变化的原因， 以确定钙调神经磷酸酶依赖性振荡在心脏健康和疾病中的作用。 具体目标1：确定钙调神经磷酸酶活性昼夜节律的潜在因素。我们 将测试是否外在因素，如身体活动，或内在因素，如心肌细胞- 自主钙振荡是钙调磷酸酶昼夜节律激活的主要原因。 具体目标2：确定钙调神经磷酸酶昼夜节律变化的机制， 依赖性活动影响心脏功能。我们将研究两种磷酸化的变化， 调节蛋白和钙调磷酸酶/NFAT途径的直接转录靶点。 具体目标3：测试正常昼夜节律的破坏是否促进病理性 心脏重塑改变的光照方案和具有改变的钙调磷酸酶活性的转基因系 将被用来扰乱正常的昼夜节律。心脏功能和存活率的变化， 动物受到压力超负荷将被评估，以及在分子的变化， 目标1和2中探索的机制。

RESEARCH SUMMARY Circadian rhythms are self-sustaining, 24-hour cycles in molecular, biochemical, and behavioral parameters that help an organism prepare for anticipated changes in physiological demand. Many important cardiovascular factors, including metabolism, heart rate, blood pressure, and hormone release, oscillate over a 24-hour period. In humans, the incidence of adverse cardiac events, such as myocardial infarction, ventricular tachycardia, and death from ischemic heart disease, vary according to the time of day, and forced changes in circadian rhythm are associated with increased risk for heart failure. Cardiovascular disease is the major cause of death in the United States and its incidence is reaching epidemic proportions worldwide. Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling. We have recently found evidence of large circadian oscillations in the activity of the calcium-activated protein phosphatase calcineurin in normal, healthy hearts. This finding is remarkable because activation of calcineurin has primarily been thought of as a pathological process driving cardiac hypertrophy and failure. We hypothesize that daily oscillations in calcineurin activity form interdependent feedback loops with other cellular processes helping to coordinate changes in cardiac function and remodeling in anticipation of changes in physiological demand. Furthermore, we postulate that disruption of the normal temporal relationship of calcineurin activity increases cardiac stress and contributes to deterioration of cardiac function. The goal of this grant is to identify the cause of circadian changes in calcineurin activity and to determine the role of calcineurin-dependent oscillations in cardiac health and disease. Specific Aim 1: To identify factors underlying the circadian rhythm in calcineurin activity. We will test whether extrinsic factors, such as physical activity, or intrinsic factors, such as cardiomyocyte- autonomous calcium oscillations are the primary cause underlying circadian activation of calcineurin. Specific Aim 2: To determine mechanisms through which circadian changes in calcineurin- dependent activities impact cardiac function. We will examine both changes in phosphorylation of regulatory proteins and direct transcriptional targets of the calcineurin/NFAT pathway. Specific Aim 3: To test whether disruption of normal circadian rhythms promotes pathological remodeling of the heart. Altered light regimens and transgenic lines with altered calcineurin activity will be used to disrupt normal circadian rhythmicity. Changes in cardiac function and survival when the animals are subjected to pressure overload will be assed as well as changes in the molecular mechanisms explored in Aims 1 and 2.