Electronic Theses and Dissertations

Date of Award

1-1-2013

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

David B Murray

Second Advisor

Samir A. Ross

Third Advisor

John Matthews

Relational Format

dissertation/thesis

Abstract

The endocannabinoid system and CB1 and CB2 cannabinoid receptors have been implicated in cardiac remodeling with CB1 inhibition and CB2 activation reported to be beneficial. However, the role of these receptors in cardiac remodeling secondary to hypertension is not known. Moreover, the functions of the CB1 and CB2 cannabinoid receptors in cardiac ventricular fibroblasts and their downstream fibrotic pathways has not yet been elucidated. This study was designed to determine the temporal myocardial expression pattern of CB1 and CB2 receptors in cardiac remodeling secondary to pressure overload (PO) induced hypertension at 3, 5, 14 and 28 days. The expression of the cannabinoid CB1 and CB2 receptors on human ventricular fibroblasts and the effects of their direct modulation on the fibrotic responses were also investigated. Rat model of pressure overload induced by abdominal aortic constriction was used for the in vivo study while the human ventricular fibroblast cell line was used for the in vitro study. The presence of CB1 and CB2 receptors was demonstrated on rat fibroblasts in left ventricular cross-sections and on human ventricular fibroblasts for the first time. Myocardial CB1 receptor levels were transiently increased at 3 days before showing decreased expression at the 14 and 28 day time points in the PO groups as compared to sham values. Myocardial CB2 receptor levels were significantly increased at the 3, 5 and 14 day time points in the PO groups as compared to sham values. Thus, the endocannabinoid system was found to be responsive to the pathophysiological changes occurring in cardiac remodeling with temporal alterations in the expression of cannabinoid receptors. CB1 receptor antagonism on human ventricular fibroblasts was found to decrease their collagen expression and production, thus having an anti-fibrotic effect while CB2 receptor antagonism was found to promote their collagen expression and production, thus having a profibrotic effect. Thus, CB1 antagonism and CB2 agonism seem to be involved in mediating a protective effect against fibrotic responses of the human ventricular fibroblasts. Modulation of these receptors could thus offer an exciting new avenue for development of anti-fibrotic therapies and attenuating adverse remodeling changes.

Concentration/Emphasis

Emphasis: Pharmacology

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