Angiogenesis, Cardiac Hypertrophy and Surgical Ischemia

描述(由申请人提供)： 在患有先天性心脏病的婴儿和儿童中，因慢性压力或容量超负荷而导致的心肌肥大仍然是心力衰竭最常见的原因之一。尽管外科手术取得了进展，但慢性高负荷状态是先天性心脏缺陷处理中常见的问题，并经常导致心脏手术造成的收缩功能障碍和对缺血的耐受性差。为了进一步探讨代偿性肥厚进展为失代偿性的机制，我们建立了一种10天龄兔主动脉缩窄的压力超负荷性肥厚模型，从代偿性肥厚发展到重度肥厚，然后是7-8周的扩张期和衰竭。伴随着这些变化的是，严重肥厚的微血管密度下降，底物输送和线粒体氧化能力受损。我们假设，在压力超负荷肥大中，对心肌细胞肥大的刺激不会导致伴随的毛细血管生长触发，从而导致底物需求与供应的失衡。此外，我们假设，作为组织中对低氧适应性变化的主要调节因子，低氧诱导因子(HIF)的活性随着肥厚进展到衰竭而降低。我们还假设，激活/上调HIF的干预措施将促进压力超负荷肥大的毛细血管生长，并将维持底物供需之间的正常平衡。为了验证这一假说，我们将追求两个相互关联的目标：目的I.测定肥厚心脏中HIF-10的活性/表达，以及治疗性HIF激活/上调对微血管密度的影响。目的II-确定线粒体功能障碍在肥厚心肌HIF-1a信号调节中的作用。这些研究将有助于更好地了解压力超负荷肥厚时发生心力衰竭的机制，并将评估预防肥厚心肌发生心力衰竭和提高对缺血耐受性的治疗策略。

DESCRIPTION (provided by applicant): In infants and children with congenital heart defects, myocardial hypertrophy in response to chronic pressure or volume overload remains one of the most common causes of heart failure. Despite surgical advances, a chronic high workload state is a common problem seen in management of congenital heart defects and often results in contractile dysfunction and poor tolerance to ischemia imposed by cardiac surgery. To further investigate mechanisms responsible for progression of compensated hypertrophy to decompensated with ventricular dilatation and failure, we have developed a model of pressure-overload hypertrophy from aortic banding of rabbits at 10 days of age, where ventricular hypertrophy progresses from compensated to severe hypertrophy, followed by ventricular dilatation and failure over a 7-8 week period. Concomitant with these changes there is a decline in microvascular density in severe hypertrophy, with impaired substrate delivery and mitochondrial oxidative capacity. We hypothesize that in pressure-overload hypertrophy, the stimulus for myocyte hypertrophy does not result in a concomitant trigger for capillary growth leading to an imbalance of substrate demand to supply. Furthermore, we postulate that activity of hypoxia inducible factor (HIF), the main regulator of adaptive changes to hypoxia in tissues, decreases as hypertrophy progresses to failure. We also postulate that interventions that activate/upregulate HIF will promote capillary growth in pressure-overload hypertrophy and will maintain the normal balance between substrate supply and demand. To test this hypothesis we will pursue two interrelated aims: aim i. determine the activity/expression of hif-1 o_in hypertrophied heart and effects of therapeutic hif activation/upregulation on microvascular density. aim ii - determine the role of mitochondrial dysfunction in regulation of hif- 1a signaling in the hypertrophied myocardium. these studies will provide an improved understanding of the mechanism responsible for the development of heart failure in pressure-overload hypertrophy and will evaluate therapeutic strategies to prevent the onset of failure and improve tolerance to ischemia in hypertrophied myocardium.