Author : Zhaobo Fan
Publisher :
Page : pages
File Size : 23,44 MB
Release : 2016
Category :
ISBN :
Myocardial infarction usually occurs after the blockage of coronary arteries. Cardiac cells are immediately exposed to a harsh environment with insufficient oxygen and nutrients. With prolonged hypoxia, the cardiomyocytes are damaged, which triggers the cardiac pathological hypertrophy, leading to the loss of heart function. Meanwhile, the cytokines are upregulated within myocardium may have negative effects in keeping the ventricular geometry. The level of transforming growth factor beta (TGFß) is increased which would drive the cardiac fibroblast differentiation into cardiac myofibroblast by activating the TGFß/ Smad signaling pathway to achieve wound healing process. However, the excessive collagen produced by myofibroblast is responsible for cardiac fibrosis. Myocardial extracellular matrix (ECM) degradation may also occur, due to the elevated matrix metalloproteinase -2 (MMP-2) concentration. The impairment of ECM may lead to wall thinning, further causing myocardial remodeling. To control cardiac fibrosis, downregulation of the TGFß signaling pathway by blocking the TGFß receptor II (TGFßRII) would be necessary. To reduce wall-thinning induced myocardial remodeling, MMP-2 activity needs to be inhibited. Small molecule based TGFßRII and MMP-2 inhibitors are widely used in current studies, but their off-target binding leads to toxicity, which largely limits their clinical use. Thermosensitive hydrogel based localized drug delivery system is attractive in heart injection for the high drug retention at the infarcted site. The drug encapsulated in the hydrogel could be released for a long period of time. In this dissertation, a MMP-2 inhibitor peptide (CTT) and a TGFßRII binding peptide (ECG) were explored and encapsulated in the hydrogel to develop drug delivery system. Both peptides could release at least 28days, and showed bioactivity. In an animal MI model, the ECM could be preserved by injecting CTT delivery system; a significant reduction of myofibroblast density was achieved by delivering ECG to the infarcted heart. Basic fibroblast growth factor (bFGF) is known for its effect in increasing cell survival, proliferation, angiogenesis, and reducing fibrosis. The study of delivering bFGF to achieve anti-fibrosis post-MI was also conducted. With increased vessel density and reduced myofibroblast, bFGF delivery system effectively controlled cardiac fibrosis and improved cardiac function. Furthermore, the effect of CTT combining with bFGF in anti-fibrosis and reducing myocardial remodeling was also investigated in vivo. To overcome the low-oxygen level microenvironment, typical of infarcted heart, an oxygen release microsphere was introduced to the ECG delivery system. This dual delivery system was shown to increase the cell survival and reduce the percentage of myofibroblast in hypoxic condition in vitro. In vivo, with additional oxygen release, the hypoxia induced fibrosis is largely reduced, which contributes to the attenuated myocardial remodeling.