Abstract
Vascular endothelial growth factor (VEGF) plays important roles in improvement of cardiac function following myocardial infarction (MI). However, the lack of a steerable delivery system of VEGF targeting the infarcted myocardium reduces the therapeutic efficacy and safety. Here, we constructed a series of lentiviral vector systems which could express a fusion protein consisted of a collagen-binding domain (CBD) and hVEGF (CBDhVEGF), under the control of 5HRE-hCMVmp (5HRE), the hypoxia-inducible promoter consists of five copies of the hypoxia-responsive element (HRE) and a human cytomegalovirus minimal promoter (hCMVmp). We demonstrated that 5HRE has the comparable ability to strongly drive CBDhVEGF under hypoxic condition as the ubiquitous CMV promoter, but it can hardly drive target gene under normoxic condition. 5HRE-drived CBDhVEGF specifically bound to type I collagen and significantly promoted the viability of HUVEC cells. Moreover, after injection of lentivirus into heart of mouse with MI, CBDhVEGF was mainly retained in infarcted myocardium where containing rich collagen and significantly improved angiogenesis and cardiac function when compared with hVEGF. Moreover, CBDhVEGF mediated by lentivirus has little leakage from infarcted zone into blood than hVEGF. Taken together, our results indicate that 5HRE-CBDhVEGF lentiviral vector system could improve cardiac function in the collagen-targeting and hypoxia-inducible manners.
Highlights
The leading cause of death in the world is coronary heart disease (CHD) which is usually caused by coronary stenosis, thereby leading to ischemic and hypoxic injury myocardium, known as myocardial infarction (MI)
In the mice acute myocardial infarction (AMI) model, we found that the CBDhVEGF driven by 5HRE could be expressed and retained in the ischemic and hypoxic myocardium, thereby improving the cardiac function by increasing the arteriole and capillary density, with the comparable capacity of that driven by the ubiquitous CMV promoter
We found that 5HRE-CBDhVEGF system is hypoxia-responsive and collagen-targeted both in vitro and in vivo
Summary
The leading cause of death in the world is coronary heart disease (CHD) which is usually caused by coronary stenosis, thereby leading to ischemic and hypoxic injury myocardium, known as myocardial infarction (MI). The previous studies indicate that HREs may be a suitable element to drive target gene expression under hypoxic conditions via combination with minimal ubiquitous or tissue specific promoters. We designed a series of lentiviral vector systems which can express hVEGF alone or a fusion protein consisting of the collagen-binding domain and hVEGF (CBDhVEGF) under the control of 5HRE-hCMVmp (5HRE) or the ubiquitous CMV promoter (see Methods and Figure S1). In the mice acute myocardial infarction (AMI) model, we found that the CBDhVEGF driven by 5HRE could be expressed and retained in the ischemic and hypoxic myocardium, thereby improving the cardiac function by increasing the arteriole and capillary density, with the comparable capacity of that driven by the ubiquitous CMV promoter
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