Role of Chymase In The Post-Myocardial Infarction Heart

食糜酶在心肌梗死后心脏中的作用

• 批准号: 8645681
• 负责人: AHSAN HUSAIN
• 金额: $ 37.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645681
• 关键词: AGTR2 gene; Acute myocardial infarction; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Area; Attenuated; Binding; Bradykinin; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Degranulation; Chemosensitization; Chymase; Collagen; Conscious; Deterioration; Development; Dilatation - action; Distal; Fibrosis; Foundations; Functional disorder; Gelatinase A; Gelatinase B; Generations; Genetic Models; Hamsters; Heart; Homologous Gene; Human; Hypertrophy; Infarction; Interruption; Kinins; Left ventricular structure; Matrix Metalloproteinases; Mediating; Minor; Mus; Myocardial Infarction; Myocardium; Outcome; Patients; Placebos; ProMMP-9; Production; Renin-Angiotensin System; Role; Serine Protease; Staging; Therapeutic Agents; Ventricular Remodeling; Wild Type Mouse; attenuation; improved; in vivo; inhibitor/antagonist; interstitial; mast cell; mast cell protease 4; mortality; mouse model; novel therapeutics; public health relevance; receptor

DESCRIPTION (provided by applicant): Chymase, a multifunctional mast cell serine protease, generates angiotensin (Ang) II and activates pro-matrix metalloproteinase (MMP)-2/9, in vivo, in the mouse heart. We show that combined ACE + chymase inhibition improves left ventricle (LV) function, decreases adverse cardiac remodeling, and markedly improves survival after MI (Wei et al., J Clin Invest. 120, 1229-39, 2010). However, by itself, chymase inhibition is mildly efficacious, suggesting that ACE inhibition potentiates chymase release. This is supported by the finding that ACE inhibition causes bradykinin/kinin B2 receptor-mediated release of mouse mast cell protease (MMCP)-4 (functional homolog of human chymase) in the LV interstitium in vivo. Although these findings suggest that the beneficial effects of bradykinin potentiation in the ACE-inhibitor-treated post-MI heart are counteracted by bradykinin-mediated chymase release, the downstream targets of chymase are unknown. We hypothesize that MMCP-4 release limits the cardiac efficacy of ACE inhibitor therapy in the post-MI heart because it activates pro-MMP-9 and generates Ang II. It is known that MMP-9 contributes to early post-MI LV dilatation by degrading interstitial collagen, and Ang II promotes cardiomyocyte hypertrophy and interstitial fibrosis. We will explore our hypothesis using mice with targeted deletion of MMCP-4 and/or MMP-9. In Specific Aim 1 we will demonstrate that, after a MI, MMCP-4-dependent Ang II generation limits ACE inhibitor efficacy in reducing late-stage cardiomyocyte hypertrophy and LV interstitial fibrosis in the distal LV myocardium. Ang II binds to two receptor subtypes, AT1 and AT2. ACE-inhibited WT versus MMCP-4(-/-) mice will be treated with placebo versus a combination of AT1 + AT2 receptor blockade to confirm the hypothesis that, despite ACE inhibition, MMCP-4- dependent Ang II formation is involved in late-stage cardiomyocyte hypertrophy and LV interstitial fibrosis in the post-MI heart. In Specific Aim 2 we will demonstrate that, in ACE inhibitor-treated mice with MI, attenuation of early LV interstitial collagen accumulation, LV dilatation and the rate of mortality are limited by MMCP-4- dependent pro-MMP-9 activation. In Part I of this Aim we will define the temporal relationship between mast cell degranulation, MMCP-4-dependent pro-MMP-2/9 activation, and LV dilatation in ACE-inhibitor treated post-MI hearts and relate these changes to early LV dilatation and dysfunction in the post-MI heart of ACE inhibitor-treated WT mice. In Part II of this Aim we will demonstrate that MMCP-4-dependent pro-MMP-9 activation limits the efficacy of ACE inhibitor therapy with respect to LV dilatation, function and survival in mice with MI. Such findings could explain why adding an AT1 receptor blocker to an ACE inhibitor does not improve survival outcomes over ACE inhibitor monotherapy. It suggests that chymase inhibition, rather than further interruption of the renin-angiotensin system, may be more efficacious in post-MI patients already treated with an ACE inhibitor. If the proposed hypotheses are confirmed, our findings would provide a foundation for the development of novel therapeutic agents directed toward patients with cardiovascular disease.

描述（由申请人提供）：Chymase是一种多功能肥大细胞丝氨酸蛋白酶，生成血管紧张素（ANG）II并激活pro-Matrix金属蛋白酶（MMP）-2/9，在体内，在小鼠心脏中。我们表明，ACE + CHYMASE抑制作用共同提高了左心室（LV）功能，降低心脏重塑，并在MI之后显着提高了生存率（Wei等人，J Clin Invest。120，1229-39，2010）。然而，从本身就可以有效地抑制Chymase，这表明ACE抑制会增强Chymase的释放。这一点得到了这一发现，即ACE抑制作用导致缓激肽/Kinin B2受体介导的小鼠肥大细胞蛋白酶（MMCP）-4（人类Chymase的功能同源物）在体内lv间质中。尽管这些发现表明，铁蛋白增强在ACE抑制剂治疗的MI后心脏中的有益作用是由Bradykinin介导的Chymase释放来抵消的，但Chymase的下游靶标尚不清楚。我们假设MMCP-4释放限制了MI后心脏中ACE抑制剂治疗的心脏功效，因为它激活了Pro-MMP-9并产生ANG II。众所周知，MMP-9通过降解间质胶原蛋白会导致早期MI LV扩张，ANG II促进心肌细胞肥大和间质纤维化。我们将使用针对MMCP-4和/或MMP-9的靶向缺失的小鼠探索我们的假设。在特定的目标1中，我们将证明，在MI依赖MMCP-4依赖性ANG II产生限制后，ACE抑制剂在降低远端LV心肌中的晚期心肌肥大和LV间质纤维化方面在降低晚期心肌细胞肥大和LV间质纤维化方面有效性。 ANG II与两个受体亚型AT1和AT2结合。 ACE抑制的WT与MMCP-4（ - / - ）小鼠将接受安慰剂与AT1 + AT2受体阻滞的组合治疗，以证实以下假设：尽管ACE抑制了ACE，MMCP-4-依赖性ANG II的形成与晚期心肌细胞超细胞超细胞超细胞超细胞超细胞质纤维症有关。在特定的目标2中，我们将证明，在具有MI的ACE抑制剂治疗的小鼠中，LV早期的间隙胶原蛋白积累的衰减，LV扩张和死亡率受到MMCP-4-依赖性Pro-MMP-9激活的限制。在此目标的第一部分中，我们将定义肥大细胞脱粒，MMCP-4依赖性Pro-MMP-2/9激活与ACE抑制剂治疗后MI心脏中的LV膨胀之间的时间关系，并将这些变化与早期的LV扩张和功能障碍相关联，在ACE Inibyitor-Mi Heart the Mi Inibyitor-Mi Heart the Mibyitor-theatepor-theator-heartector-preator-theator-heart thepter-mi heart中的功能障碍。在此目的的第二部分中，我们将证明MMCP-4依赖性Pro-MMP-9激活限制了ACE抑制剂治疗在MI中小鼠中LV扩张，功能和存活方面的功效。这样的发现可以解释为什么在ACE抑制剂中添加AT1受体阻滞剂不会改善ACE抑制剂单药治疗的生存结果。这表明Chymase抑制作用，而不是进一步中断肾素 - 血管紧张素系统，可能对已经接受ACE抑制剂治疗的MI后患者更有效。如果提出的假设得到确认，我们的发现将为开发针对心血管疾病患者的新型治疗剂的发展提供基础。

项目成果

Insights into the characteristics of mammalian cardiomyocyte terminal differentiation shown through the study of mice with a dysfunctional c-kit.

• DOI: 10.1007/s00246-008-9366-1
• 发表时间: 2009-07
• 期刊: PEDIATRIC CARDIOLOGY
• 影响因子: 1.6
• 作者: Naqvi, Nawazish;Li, Ming;Yahiro, Eiji;Graham, Robert M.;Husain, Ahsan
• 通讯作者: Husain, Ahsan

Cardiomyocytes Replicate and their Numbers Increase in Young Hearts.

• DOI: 10.1016/j.cell.2015.10.038
• 发表时间: 2015-11-05
• 期刊: Cell
• 影响因子: 64.5
• 作者: Naqvi N;Singh R;Iismaa SE;Li M;Calvert JW;Martin DI;Harvey RP;Graham RM;Husain A
• 通讯作者: Husain A