Date of Award

2012

Degree Name

Biomedical Sciences

College

College of Liberal Arts

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Eric R. Blough

Second Advisor

Monica A. Valentovic

Third Advisor

Todd L. Green

Fourth Advisor

Nalini Santanam

Fifth Advisor

Robert O. Harris

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by inflammation, increased pulmonary vascular resistance, right ventricular failure and premature death. Monocrotaline (MCT) has been used to induce PAH in laboratory rats. Previous in vitro and in vivo work suggested that cerium oxide (CeO2)-and curcumin nanoparticles exhibit anti-inflammatory activity; however, it is unknown if these materials are effective for the treatment of PAH induced cardiac hypertrophy. To determine the efficacy of CeO2 nanoparticle treatment in preventing MCT-induced RV hypertrophy, male Sprague Dawley rats were divided into one of three groups (control, MCT, or MCT + CeO2 nanoparticle, n=6/group). MCT was administered at a dosage of 60mg/kg subcutaneously. CeO2 nanoparticle treated animals received 0.1mg/kg via tail vein injection twice a week for two weeks. Echocardiography was performed before and at the completion of the study. CeO2 nanoparticles treatment attenuated MCT-induced increases in RV mass, cardiomyocyte cross sectional area, and diminished cardiac oxidative stress levels. These changes in cardiac structure and oxidative stress were accompanied by decreased mitogen activated protein kinase phosphorylation, diminished heat shock proteins expression, improvements in the Bax/Bcl-2 ratio, and diminished caspase-3 activation. To investigate the efficacy of curcumin nanoparticle (Cur NP) administration in preventing PAH-induced cardiac remodeling after pulmonary arterial hypertension, rats were divided into one of three groups (control, MCT, or MCT + Cur NP treatment, n=6/group). MCT was injected at a dosage of 60mg/kg subcutaneously. Nanoparticle treated animals received Cur NP (50mg/kg i.p.) for seven days. Cur NP treatment diminished MCT-induced increases in pulmonary arterial pressures, RV thickness and myocardial fibrosis. These changes in cardiac structure were accompanied by down regulation of myosin heavy chain (MCH-β) and fibronectin protein. Cur NP treatment also reduced expression of tissue tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) mRNA levels, decreased heat shock protein expression and reduced the amount of protein nitrosylation. Taken together, the results of these studies suggest that administration of CeO2/curcumin nanoparticles may attenuate the degree of cardiac remodeling typically observed following the development of pulmonary arterial hypertension in the laboratory rat. Additional studies to investigate the mechanism(s) underlying these changes may be warranted. (WC: 349)

Subject(s)

Pulmonary artery - Diseases.

Cerium oxides.

Curcumin - Therapeutic use.