Date of Award

1-1-2013

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Scott C Supowit

Abstract

Heart failure (HF) still remains the leading cause of morbidity and mortality and imposes severe global affliction and enormous cost on the healthcare system. Although current pharmacological therapies have shown to slow down the progression of HF, but seems to have reached their limits in improving overall patient prognosis. Thus, an immediate call for novel alternate therapies are needed which act independently as well as in conjunction with current treatment modality. Studies were performed in the well-established transverse aortic constriction (TAC) model of chronic pressure overload (PO) in mice. In the first series of studies, Male C57BL6 mice (26-28 g) were subjected to either sham or TAC surgery. One group of TAC mice was given daily resveratrol treatment (oral gavage, 100 mg/kg/body weight (bw) for 28 days starting on day 2 after surgery. Echocardiographic, biometric, and immunohistological analyses were performed on the three groups of mice which demonstrated significantly greater adverse cardiac remodeling and dysfunction in the TAC compared to the sham operated mice. These pathological changes were significantly improved by resveratrol treatment in TAC+RSV mice. At day 28 fractional shortening was 46.4±2.4%, 26.2±1.0%, and 35±2% in the sham, TAC, and TAC +RSV mice, respectively. This was reflected by lung weight/bw ratios of 4.8±0.5 mg/g (sham), 10.2±1.4 mg/g (TAC) and 6.2±1.5 mg/g (TAC+RSV). Resveratrol treatment also significantly reduced cardiac hypertrophy as determined by the heart weight/bw ratios (sham, 4.9±0.3 mg/g; TAC, 8.8±1.1 mg/g; and TAC+RSV, 7.2±0.3 mg/g) as well as by measurement of cross-sectional area (CSA) (sham, 108.02±12.85 µm²; TAC, 221.7±21.43 µm²; and TAC+RSV, 187±11.9 µm²). Likewise, the TAC protocol significantly increased fibrosis compared to the sham-operated mice, which was attenuated by resveratrol treatment. Pro-inflammatory cytokine infiltration of mast cells and macrophage were found up-regulated in response to PO. Similarly, markers of oxidative stress such as 4-hydroxynonenal (4HNE) and 8-hydroxydeoxyguanosine (80HdG) were up regulated while anti oxidative markers -sodium oxidase dismutase (SOD), glutathione peroxidase (GSH) were down regulated in response to PO. Similar results were obtained when hypoxia induced factor alpha (HIF1α), including apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and activated caspase-3 were assessed in TAC hearts. These TAC-induced factors were significantly attenuated by resveratrol treatment indicating that the resveratrol was acting to inhibit the increased production of these stress inducible factors as well as able to up regulate the levels of detoxifying enzymes. In summary, these results demonstrate that resveratrol treatment significantly attenuates the adverse cardiac remodeling and dysfunction produced by the TAC protocol in C57/BL6 mice and that this activity is mediated, at least in part, by the inhibition of oxidative stress and hypoxia.

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