Inflammatory serine proteases and cardiac repair post myocardial infarction

炎症性丝氨酸蛋白酶与心肌梗死后的心脏修复

• 批准号: 9259812
• 负责人: AbdelKarim Sabri
• 金额: $ 39万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259812
• 关键词: Acute myocardial infarction; Adaptor Signaling Protein; Adult; Affect; Area; Atherosclerosis; Birth; Cardiac; Cardiac Myocytes; Cardiovascular system; Cathepsin C; Cathepsin G; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Cicatrix; Coronary heart disease; Data; Defect; Development; Disease; Down-Regulation; Drug Kinetics; Enzymes; Exposure to; Genetic; Goals; Growth; Heart; Heart Diseases; Heart failure; Human; Immune system; Immunologics; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interleukin-2; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardial tissue; Myocardium; Natural regeneration; Neonatal; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Process; Proteins; Rattus; Reaction; Receptor Protein-Tyrosine Kinases; Role; Serine Protease; Signal Transduction; Site; Stem cells; System; Testing; Therapeutic; Time; Tissues; Ubiquitin; adaptive immunity; cardiac regeneration; cardiac repair; cell growth; drug distribution; heart cell; improved; in vivo; inhibitor/antagonist; injured; leukocyte activation; mortality; multicatalytic endopeptidase complex; nanocarrier; neonatal exposure; neutrophil; novel; novel strategies; public health relevance; regenerative; repaired; response; response to injury; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): In the adult heart, cell death following myocardial infarction (MI) initiates an inflammatory reaction that removes dead cells and contributes to scar formation and cardiac repair. Since the regenerative capacity of the adult mammalian heart is limited, induction of this innate immune response could be maladaptive and compromises cardiac contractile function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is largely lost rapidly after birth. A proactive role of the immune system and its response to injury has been proposed to be a central mediator of neonatal heart regeneration. However, the exact mechanisms by which neonatal adaptive immunity modulates heart regeneration are largely unknown. We found that induction of MI in post-natal day 1 (P1) mice induced an inflammatory response that failed to activate key inflammatory serine proteases (ISPs), enzymes released upon leukocyte activation and are the primary reason for tissue damage at the sites of inflammation. In contrast, activation of ISPs was observed when MI was performed at P7 or later, a time when the regenerative capability of the heart is very low. Because activation of ISPs occurs early after myocardial injury, is an important regulator of the inflammatory response and functionally modulates a number of protein substrates that regulate cell growth and function, we hypothesize that activation of ISPs plays an active role in regulating cardiac regeneration and repair. Pilot study shows that inhibition of ISPs in vivo using mice deficient in DiPeptidyl Peptidase I (DPPI), a key enzyme necessary for the cleavage and activation of major ISPs, enhanced cardiomyocyte proliferation during post-natal development and in adult hearts subjected to MI compared to wild-type, along with an improvement in cardiac remodeling and function. Interestingly, DPPI deletion also enhanced the survival of stem cells in the infarcted area, suggesting that ISPs modulate post-MI repair by affecting not only cardiomyocyte growth and proliferation, but also by modulating stem cell survival and growth. These data support the hypothesis that activation of ISPs impairs endogenous cardiac repair and leads to cardiac dysfunction post-MI. Here, we will determine whether inhibition of ISPs enhances endogenous cardiac repair and regeneration in neonatal and adult heart after MI injury. We will also define the mechanisms by which ISPs modulate cardiac regeneration of neonatal and adult hearts. The long term goal is to develop novel strategies targeting DPPI to enhance cardiac repair after MI, for which not a single drug is currently available.

 描述（由申请人提供）：在成人心脏中，心肌梗死（MI）后的细胞死亡引发炎症反应，清除死细胞并促进瘢痕形成和心脏修复。由于成年哺乳动物心脏的再生能力是有限的，这种先天性免疫反应的诱导可能是适应不良的，并损害心脏收缩功能。在新生小鼠中，心肌梗死后心脏可以完全再生而不会留下疤痕;然而，这种再生能力在出生后很快就会丧失。免疫系统的主动作用及其对损伤的反应已被认为是新生儿心脏再生的中心介体。然而，新生儿适应性免疫调节心脏再生的确切机制在很大程度上是未知的。我们发现，在出生后第1天（P1）小鼠中诱导MI诱导了炎症反应，该炎症反应未能激活关键的炎症性丝氨酸蛋白酶（ISP），即白细胞激活后释放的酶，并且是炎症部位组织损伤的主要原因。相反，当在P7或更晚时进行MI时，观察到ISP的激活，此时心脏的再生能力非常低。由于ISPs的激活发生在心肌损伤后早期，是炎症反应的重要调节因子，并在功能上调节许多调节细胞生长和功能的蛋白质底物，我们假设ISPs的激活在调节心脏再生和修复中起着积极的作用。初步研究表明，与野生型相比，使用二肽基肽酶I（DPPI）缺陷的小鼠体内抑制ISP（DPPI是主要ISP裂解和活化所必需的关键酶）增强了出生后发育期间和患有MI的成年心脏中的心肌细胞增殖，沿着心脏重塑和功能的改善。有趣的是，DPPI缺失也增强了梗死区干细胞的存活，表明ISP不仅通过影响心肌细胞的生长和增殖，而且通过调节干细胞的存活和生长来调节MI后修复。这些数据支持这样的假设，即ISP的激活损害内源性心脏修复并导致MI后心功能障碍。在这里，我们将确定是否抑制ISPs增强心肌梗死损伤后新生儿和成人心脏的内源性心脏修复和再生。我们还将确定ISPs调节新生儿和成人心脏再生的机制。长期目标是开发靶向DPPI的新策略，以增强MI后的心脏修复，目前尚无单一药物可用。