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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
7R15HL066016-02
Application #
7147771
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2006-01-25
Budget End
2007-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$37,530
Indirect Cost
Name
Texas A&M University
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
141582986
City
College Station
State
TX
Country
United States
Zip Code
77845
Chopra, Mani; Golden, Honey B; Mullapudi, Srinivas et al. (2011) Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat. PLoS One 6:e21285
Chopra, Mani; Das, Padmalaya; Golden, Honey et al. (2010) Norepinephrine induces systolic failure and inhibits antiapoptotic genes in a polymicrobial septic rat model. Life Sci 87:672-8
Das, Padmalaya; Chopra, Mani; Sun, Yao et al. (2009) Age-dependent differential expression of apoptosis markers in the gingival tissue. Arch Oral Biol 54:329-36
Chopra, Mani; Sharma, Avadhesh C (2009) Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart. Pharmacol Res 60:303-13
Sharma, Avadhesh C (2007) Sepsis-induced myocardial dysfunction. Shock 28:265-9
Chopra, Mani; Sharma, Avadhesh C (2007) Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction. Life Sci 81:306-16
Chopra, Mani; Sharma, Avadhesh C (2007) Apoptotic cardiomyocyte hypertrophy during sepsis and septic shock results from prolonged exposure to endothelin precursor. Front Biosci 12:3052-60
Gupta, Akanksha; Aberle 2nd, Nicholas S; Ren, Jun et al. (2005) Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis. J Mol Cell Cardiol 38:527-37
Gupta, Akanksha; Brahmbhatt, Sachin; Kapoor, Ruchita et al. (2005) Chronic peritoneal sepsis: myocardial dysfunction, endothelin and signaling mechanisms. Front Biosci 10:3183-205
Gupta, Akanksha; Aberle 2nd, Nicholas S; Kapoor, Ruchita et al. (2005) Bigendothelin-1 via p38-MAPK-dependent mechanism regulates adult rat ventricular myocyte contractility in sepsis. Biochim Biophys Acta 1741:127-39

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