Endothelin Converting Enzyme in Sepsis: Cardiac Function

脓毒症中的内皮素转换酶：心脏功能

• 批准号: 7147771
• 负责人: AVADHESH C SHARMA
• 金额: $ 3.75万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147771
• 关键词: aspartic endopeptidases; cardiac myocytes; cardiovascular injury; endothelin; heart function; laboratory rat; mitogen activated protein kinase; muscle proteins; myocardium disorder; nitric oxide synthase; pathologic process; protease inhibitor; septicemia; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term objective of our group is to characterize an interactive role of vasoactive substances in sepsis-induced myocardial dysfunction and related cardiovascular pathologies. Chronic peritoneal sepsis in our rat model produces myocardial dysfunction in an isolated heart preparation and cardiomyocytes. Induction of sepsis also increases susceptibility of the isolated hearts to a calcium paradox-mediated myocardial injury. In vivo, we have demonstrated that induction of sepsis results in disproportionate alterations in the circulating levels of Endothelin-1 (ET-1) and nitric oxide byproducts (nitrite and nitrate, NOx). Recently we observed that inhibition of metalloprotease (endothelin-converting enzyme [ECE], which converts proET-1 to ET-1) at the time of induction of endotoxemia decreased the expression of myocardial inducible nitric oxide synthase (iNOS) and downregulated the expression of p38 mitogen-activated protein kinase (MAPK) twenty-four hours later. Therefore, our immediate objective in the present proposal is to test the hypothesis that sepsis-induced alteration in the biosynthesis of myocardial ET-1 (regulated by ECE-1) via MAPK-dependent or -independent mechanism(s) would affect NOS proteins and cardiac function. The following two specific aims are designed to address this hypothesis. Specific Aim 1: To determine if ECE-1 inhibition at the time of induction of sepsis would affect sepsis-induced myocardial dysfunction (decrease in the rates of left ventricular contraction and relaxation, i.e., + dP/dt and -dP/ dt respectively) and the expression of p38MAPK and iNOS proteins at 12 and 24 h post sepsis (Year 1-2). Specific Aim 2: To determine if ECE-1 inhibition at the time of induction of sepsis via p38MAPK-dependent or -independent mechanism would affect myocardial function in an isolated heart preparation at 24 h post sepsis (Year 2-3). The specific aims were designed to assess if ECE-1 inhibition during sepsis would suppress sepsis-induced myocardial dysfunction characterized by downregulation of p38 MAPK and depressed expression of iNOS proteins. The novel aspect of the specific aims is that the results will provide evidence for a causal relationship between ET-1 biosynthesis and the expression of p38MAPK and iNOS proteins in the myocardium. An increased understanding of the underlying mechanisms during these two stages (12 and 24 h post sepsis) of sepsis will help design therapeutic interventions for early and late stages of sepsis.

描述（由申请人提供）：我们小组的长期目标是表征血管活性物质在脓毒症诱导的心肌功能障碍和相关心血管病理中的相互作用。慢性腹膜脓毒症在我们的大鼠模型产生心肌功能障碍，在一个孤立的心脏准备和心肌细胞。脓毒症的诱导也增加了离体心脏对钙反常介导的心肌损伤的易感性。在体内，我们已经证明，诱导脓毒症的结果在内皮素-1（ET-1）和一氧化氮副产物（亚硝酸盐和硝酸盐，NOx）的循环水平的不成比例的改变。 最近，我们观察到，在诱导内毒素血症时抑制金属蛋白酶（内皮素转换酶[ECE]，其将proET-1转化为ET-1），降低心肌诱导型一氧化氮合酶（iNOS）的表达，并在24小时后下调p38丝裂原活化蛋白激酶（MAPK）的表达。因此，我们在本提案中的直接目标是验证脓毒症诱导的心肌ET-1生物合成（由ECE-1调节）通过MAPK依赖性或非依赖性机制的改变将影响NOS蛋白和心脏功能的假设。以下两个具体目标旨在解决这一假设。 具体目标1：为了确定在诱导脓毒症时ECE-1抑制是否会影响脓毒症诱导的心肌功能障碍（左心室收缩和舒张速率的降低，即，+ dP/dt和-dP/ dt）以及脓毒症后1 - 2和24 h（1-2年）p38 MAPK和iNOS蛋白的表达。 具体目标二：确定通过p38 MAPK依赖性或非依赖性机制诱导脓毒症时ECE-1抑制是否会影响脓毒症后24 h（2-3年）离体心脏制备物中的心肌功能。 具体的目的是评估在脓毒症过程中ECE-1抑制是否会抑制脓毒症诱导的心肌功能障碍，其特征在于下调p38 MAPK和抑制iNOS蛋白的表达。本研究的目的在于为ET-1生物合成与心肌组织中p38 MAPK和iNOS蛋白表达之间的因果关系提供证据。对脓毒症这两个阶段（脓毒症后12和24小时）的潜在机制的进一步了解将有助于设计脓毒症早期和晚期的治疗干预措施。

项目成果

Age-dependent differential expression of apoptosis markers in the gingival tissue.

牙龈组织中凋亡标志物的年龄依赖性差异表达。

• DOI: 10.1016/j.archoralbio.2009.01.008
• 发表时间: 2009
• 期刊: Archives of oral biology
• 影响因子: 3
• 作者: Das,Padmalaya;Chopra,Mani;Sun,Yao;Kerns,DavidG;Vastardis,Sotirios;Sharma,AvadheshC
• 通讯作者: Sharma,AvadheshC

Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart.

• DOI: 10.1016/j.phrs.2009.04.009
• 发表时间: 2009-10
• 期刊: PHARMACOLOGICAL RESEARCH
• 影响因子: 9.3
• 作者: Chopra, Mani;Sharma, Avadhesh C.
• 通讯作者: Sharma, Avadhesh C.

Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.

• DOI: 10.1371/journal.pone.0021285
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chopra M;Golden HB;Mullapudi S;Dowhan W;Dostal DE;Sharma AC
• 通讯作者: Sharma AC