Angiotensinogen (Ao) and other components of the local cardiac renin-angiotensin system (RAS) are upregulated in the hemodynamically overloaded heart. The importance of the RAS in the pathophysiology of heart failure has been highlighted by the vast number of clinical and experimental investigations, in which progression of the heart failure is associated with a steady increase in myocardial Ao expression and the biological peptide angiotensin II (Ang II) formation. Elevated cardiac Ang II alone induced cardiac interstitial fibrosis under basal conditions and exacerbated cardiac remodeling and dysfunction and accelerated development of heart failure in mice with myocardial infarction, without affecting systemic hemodynamics. In the past funding cycle, we reported 21 integrin to be a key mechanosensor. Using a combination of molecular and pharmacologic approaches also identified a number of key downstream effectors which positively and negatively couple to mechanical stretch-induced Ao gene expression in cardiac myocytes and fibroblasts. Two critical effectors were found to be JNK1 and p381, which are both regulated by 21 integrin, but have opposing roles on stretch-induced Ao expression in both cell types. In stretched cells p38 was demonstrated up upregulate Ao expression, whereas under both stretch and non-stretch conditions, JNK was negative regulator of Ao expression. In time-course experiments, prolonged stretch causes an imbalance in activation of JNK1 and p381, resulting in up-regulation of Ao gene expression in cardiac cells. Although mechanical stretch has demonstrated to activate stress-activated protein kinases for over a decade, many of the mechanisms leading to activation of these kinases and cross-talk between these signaling molecules remain to be determined. The goal of this renewal application is to further elucidate the contributory role and underlying primary mechanisms responsible for mechanical load induced temporal regulation of p38 and JNK using a combination of in vitro and in vivo models.
In Aim 1, we characterize the mechanisms by which 21 integrin and other 2 integrins couple mechanical stretch to activation of JNK, p38 and Akt and determine the role of these interactions on regulation of Ao gene expression in primary cultures of cardiac myocytes and fibroblasts. These studies will involve the role of caveolins and in mediating regulation of JNK and p381, as well as temporal regulation of the cross-talk mechanisms that comprise this regulatory circuit.
In Aim 2, we will compare the roles of JNK, p38 and Akt in regulation of Ao in the hemodynamically overloaded myocardium. These in vivo studies will be performed using a combination of pharmacological and genetic approaches in various mouse models.

Public Health Relevance

The incidence of heart failure continues to increase and is the leading cause of human morbidity and mortality in both men and women. Despite decades of intensive research and recent advances in its clinical management, it is still a disease with a poor prognosis and the most expensive single diagnosis in United States health care system. Accordingly, heart failure remains an important topic of research in need of further studies to delineate its molecular pathogenesis and to develop new diagnostic markers and therapeutic targets. This research project will help improve our understanding of the mechanical signaling pathways which contribute to this pathological disorder, may facilitate the development of new measures to prevent or more effectively treat this common and life-threatening disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL068838-07
Application #
8197462
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2001-08-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$312,922
Indirect Cost
$62,922
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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