Behavioral, dietary and pharmacological modalities of cardioprotection

心脏保护的行为、饮食和药理学方式

• 批准号: 7964069
• 负责人: Mark Talan
• 金额: $ 19.2万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964069
• 关键词: Acute myocardial infarction; Affect; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Area; Attenuated; Behavioral; Biological Factors; Blueberries; Caliber; Caloric Restriction; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic; Coronary; Coronary artery; Coupling; Developed Countries; Development; Diabetes Mellitus; Diastole; Diastolic heart failure; Diet; Disease; Dobutamine; EFRAC; Echocardiography; Elderly; Evaluation; Event; Experimental Models; Exposure to; Fasting; Fibrosis; Food; Food deprivation (experimental); Functional disorder; Harvest; Heart; Heart Atrium; Heart failure; Histologic; Hour; Human; Hypertrophy; In Situ Nick-End Labeling; Incidence; Inflammation; Inflammatory Response; Injury; Ischemia; Ischemic Brain Injury; Kidney Diseases; Left; Left Ventricular Function; Left Ventricular Remodeling; Ligation; Longevity; Malignant Neoplasms; Measurement; Measures; Mediating; Mitochondria; Modality; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neurologic; Operative Surgical Procedures; Permeability; Play; Property; Pump; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reporting; Risk; Rodent Model; Role; Signal Pathway; Stress Tests; Testing; Therapeutic Agents; Time; Tissues; Treatment Protocols; Ventricular; Withdrawal; adiponectin; aged; design; dietary antioxidant; feeding; fitness; fruits and vegetables; glycemic control; hemodynamics; improved; indexing; interest; interstitial; male; morphometry; mortality; myocardial infarct sizing; novel; pre-clinical; pressure; programs; research study; success; translational study

The broad objective of this program is to perform preclinical experimentation on rodent models of myocardial ischemia to test the effect of dietary manipulations prior to ischemic event to increase the tolerance of the cardiac tissue to ischemic damage. I. Intermittent Fasting (IF), i.e., the feeding regimen when ad lib food is available only every other day, had been reported to increase the life span and to reduces the incidence of age-associated diseases including cancer, diabetes and kidney disease. Neuroprotective effects of IF against ischemic injury of the brain have also been reported. We investigated the cardioprotective effect of IF in rats using the model of experimental myocardial infarction induced by a permanent coronary ligation. After three months of IF or regular, daily, feeding ad libitum (AF), 5-mo old rats were subjected to coronary ligation or sham operation. A subset of rats was sacrificed 24 hours later to measure the size of myocardial infarction (MI) and the extent of apoptosis. The remainder of the animals were continued for 10 weeks on the same food regimen, during which time the progression of left ventricular (LV) remodeling was assessed by serial echocardiography. After ten weeks LV function was measured by pressure-volume loops analyses, and hearts were evaluated histologically. We showed that 24 hrs following coronary ligation the ischemic area of myocardium, i.e., the area at risk (AAR), was similar in both groups, but in IF rats MI size, expressed as a percent of AAR, was more than 2-fold smaller, apoptosis in the AAR was reduced by more than 4-fold, and the inflammatory response was significantly reduced. At 10-wks, late LV remodeling and MI expansion occurred in AF rats but not in IF rats, and LV pump function and arterio-ventricular coupling were superior in IF vs AF rats. The myocyte hypertrophy in areas remote from the MI was also absent in IF rats. The results indicate that Intermittent Food Deprivation protects the heart from ischemic injury in part, at least, via an enhanced anti-apoptotic mechanism. In the last experiments we demonstrated that IF improves glycemic control and results in the increase of the levels of circulating adiponectin. Because recent studies have shown that adiponectin can protect the heart against ischemic injury, adiponectin may mediate, at least in part, the cardioprotective effect of IF. While tissue protective properties of IF have been proven, the effects chronic IF on general cardiovascular fitness remained unknown. At 4-mo of age male SD rats were started on IF or continued on ad libitum diets. Heart morphometry and function was followed for 6 months with serial echocardiography. At the end of the observation period rats were subjected to a comprehensive hemodynamic evaluation via pressure-volume loop analyses including a combined dobutamine - volume stress test, and hearts were harvested for histological assessment. The six-month long IF resulted in a 9% reduction (p<0.01) of cardiomyocyte diameter and 3 fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected in IF and ejection fraction was not reduced. Left atrial diameter was 16% increased in IF while E/A ratio in Doppler-measured mitral flow was reduced. Pressure-volume loop analyses in IF revealed a stiff heart during diastole, and histological analyses demonstrated a 3-fold increase of myocardial fibrosis vs control hearts. Combined dobutamine and volume loading showed a significant reduction in LV diastolic compliance and a lack of increase in systolic pump function in IF, indicating a diminished cardiac reserve. Thus chronic IF in rats results in development of diastolic dysfunction with diminished cardiac reserve. Therefore, IF is a novel and unique experimental model of behaviorally induced diastolic heart failure. The deleterious effect of IF in rats warrants additional studies of IF effect on cardiovascular functions in humans. II. Blueberry supplement. Reactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. However, the attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in antioxidants found in natural products. Blueberries have the highest antioxidant capacity among fruits and vegetables, and had been shown to reduce neurological deficits observed in aged animal models. The objective of this study was to assess the cardioprotective properties of a blueberry enriched diet (BD). Following 3-mo exposure to BD or a regular control diet (CD), the threshold for mitochondrial permeability transition (tMPT) was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001) of ROS indexed tMPT. The remaining animals were subjected to a permanent ligation of descending coronary artery. 24 hrs later resulting myocardial infarction (MI) in rats on BD was 24% less than in CD rats (p<0.05). Significantly less TUNEL(+) cardiomyocytes (2% vs 9%) and 40% less inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.05). In other groups of rats, immediately after coronary ligation, the original diet was either continued or switched to the opposite one, and their cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Results of echo measurements indicated that rates of post MI cardiac remodeling and MI expansion were proportional to original myocardial damage governed by the previous diet. However, BD or its withdrawal after MI induction, attenuated or accelerated this effect. We concluded that a blueberry-enriched diet protected the myocardium from ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.

该项目的主要目的是对心肌缺血的啮齿动物模型进行临床前实验，以测试缺血事件发生前饮食操作对增加心脏组织对缺血性损伤的耐受性的影响。 I.间歇性禁食（IF），即，据报道，每隔一天才能随意进食的喂养方案可以延长寿命，减少与年龄有关的疾病，包括癌症、糖尿病和肾病的发病率。IF对脑缺血性损伤的神经保护作用也有报道。我们研究了IF的心脏保护作用，在大鼠的实验性心肌梗死模型由一个永久性结扎冠状动脉。在三个月的IF或定期，每天，随意喂养（AF），5月龄大鼠进行冠状动脉结扎或假手术。24小时后处死一组大鼠，以测量心肌梗死（MI）的大小和细胞凋亡的程度。其余动物继续以相同的食物方案喂养10周，在此期间通过连续超声心动图评估左心室（LV）重构的进展。10周后，通过压力-容积环分析测量LV功能，并对心脏进行组织学评价。我们发现冠脉结扎后24小时，心肌缺血区，即，两组的危险面积（AAR）相似，但IF大鼠的MI大小（以AAR的百分比表示）小2倍以上，AAR中的凋亡减少4倍以上，并且炎症反应显著减少。10周时，AF大鼠出现晚期左室重构和MI扩张，但IF大鼠没有，IF大鼠的左室泵功能和动静脉偶联上级AF大鼠。在IF大鼠中，远离MI的区域的肌细胞肥大也不存在。结果表明，间歇性食物脱镁保护心脏免受缺血性损伤，至少部分是通过增强的抗凋亡机制。在最后的实验中，我们证明了IF改善血糖控制并导致循环脂联素水平的增加。 由于最近的研究表明，脂联素可以保护心脏免受缺血性损伤，脂联素可能介导，至少部分，IF的心脏保护作用。 虽然IF的组织保护特性已被证明，但慢性IF对一般心血管健康的影响仍不清楚。 在4月龄时，雄性SD大鼠开始接受IF或继续随意饮食。 心脏形态和功能随访6个月，连续超声心动图。在观察期结束时，通过压力-容积环分析（包括多巴酚丁胺-容积负荷试验）对大鼠进行全面的血液动力学评价，并收获心脏进行组织学评估。6个月的IF导致心肌细胞直径减少9%（p<0.01），间质心肌纤维化增加3倍。 IF患者左心室腔大小未受影响，射血分数未降低。IF患者左房内径增加16%，而多普勒测量二尖瓣血流的E/A比值降低。 IF中的压力-容积环分析显示，心脏僵硬，组织学分析表明心肌纤维化比对照心脏增加3倍。联合多巴酚丁胺和容量负荷显示左室舒张期顺应性显著降低，IF的收缩期泵功能缺乏增加，表明心脏储备减少。因此，大鼠慢性IF导致心脏储备减少的舒张功能障碍的发展。 因此，IF是一种新颖而独特的行为诱导舒张性心力衰竭的实验模型。IF在大鼠中的有害作用需要进一步研究IF对人类心血管功能的影响。 二.蓝莓补充剂 活性氧在缺血性心肌损伤中起重要作用。然而，使用合成抗氧化剂来阻断ROS的有害作用的尝试产生了混合或负面的结果，从而引起了人们对天然产品中发现的抗氧化剂的兴趣。蓝莓在水果和蔬菜中具有最高的抗氧化能力，并已被证明可以减少老年动物模型中观察到的神经缺陷。本研究的目的是评估蓝莓强化饮食（BD）的心脏保护特性。暴露于BD或常规对照饮食（CD）3个月后，在从年轻雄性Fischer-344大鼠获得的分离心肌细胞中测量线粒体通透性转换（tMPT）的阈值。与CD相比，BD导致ROS指数tMPT增加24%（p<0.001）。对其余动物进行冠状动脉降支永久结扎。24小时后，BD组大鼠心肌梗死（MI）发生率比CD组低24%（p<0.05）。与CD大鼠相比，在处于BD风险的心肌区域中观察到显著更少的TUNEL（+）心肌细胞（2%对9%）和40%更少的炎症细胞（p<0.05）。在其他组大鼠中，冠状动脉结扎后，立即继续原饮食或切换到相反的一个，他们的心脏重塑和MI扩张，随后连续超声心动图10周。超声心动图测量结果表明，心肌梗死后心脏重塑和心肌梗死扩大率与先前饮食引起的原始心肌损伤成正比。然而，BD或MI诱导后停药，减弱或加速了这种作用。我们的结论是富含蓝莓的饮食可以保护心肌免受缺血性损伤，并显示出减轻心肌梗死后慢性心力衰竭发展的潜力。