Abstract/Details

Role of ErbB (EGFR) tyrosine kinase receptors in adult and aging heart


2008 2008

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Abstract (summary)

Aging is considered as a major risk factor for heart failure. Multiple factors are involved in aging-related cardiac dysfunction. The epidermal growth factor (EGF) signaling pathway is one of those implicated to be important in aging-related cardiac and neural dysfunction and invasiveness of breast carcinoma. Blockade of signaling of ErbB-2/ErbB-4 tyrosine kinase receptors or the ligand, heparin-binding EGF leads to cardiac dysfunction. ErbB-1 may protect the heart against stress-induced injury and its ligand, EGF increases myocardial contractility. However, the role of ErbB-1 receptors in adult and aging heart is not clear. The goal of this thesis was to investigate ErbB-1 signaling in the aging heart and its contribution in the maintenance of adult cardiac function. We found that ErbB expression in aging mouse hearts was attenuated at transcriptional, translational and post-translational levels accompanied by decreased cardiac function. Using the ecdysone-inducible gene expression system, we expressed dominant-negative ErbB-1 mutant receptors (hErbB-1-mut) that block endogenous cardiac ErbB-1 signaling specifically in cardiomyocytes of young adult mice. hErbB-1-mut expression led to blockade of endogenous ErbB-1/ErbB-2 phosphorylation. Increase in left ventricular (LV) mass, atrial natriuretic factor expression and histological changes were indicative of cardiac hypertrophy as seen in the aged mice. Cardiac dilation, numerous cardiac lesions and loss of clear boundary between cardiac fibrils were noted histologically. Early and long-term hErbB-1-mut induction led to a significant decrease in fractional shortening, and a significant increase in LV end-systolic diameter as seen in aged mice and this was reversed by discontinuation of the inducer. Survival rate of transverse-aortic constricted hErbB-1-mut mice was significantly reduced. Dobutamine stimulation led to blunted inotropic responses while adenylyl cyclase stimulation normalized the depressed cardiac function. Collectively, these observations indicate that attenuation of cardiac ErbB-1 signaling leads to cardiac dysfunction as seen in aged hearts. Conversely, ErbB-1 is important for the maintenance of normal adult cardiac function and this regulatory role may be compromised in aging myocardium leading to abnormal cardiac function seen in the aged population.

Indexing (details)


Subject
Molecular biology;
Physiology
Classification
0307: Molecular biology
0433: Physiology
Identifier / keyword
Biological sciences; Aging; Cardiac function; EGFR; ErbB; Heart
Title
Role of ErbB (EGFR) tyrosine kinase receptors in adult and aging heart
Author
Rajagopalan, Viswanathan
Number of pages
199
Publication year
2008
Degree date
2008
School code
0367
Source
DAI-B 69/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549812616
Advisor
Zucker, Irving H.
University/institution
University of Nebraska Medical Center
University location
United States -- Nebraska
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3328242
ProQuest document ID
304428226
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304428226
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