Abstract
Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48–72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.
Highlights
Coronary heart disease (CHD) is the umbrella term for pathologies affecting the ability of the epicardial coronary arteries to provide oxygenated blood and nutrients to the heart (Vogel et al, 2019)
In a rat model of myocardial ischemia with reperfusion, we found that intra-arterial treatment with Hepatocyte Growth Factor (HGF)/ IgG complexes significantly improved vascular integrity and cardiac function (Rao et al, 2015)
Our results in adult pigs demonstrated that intra-arterially administered HGF/IgG complexes distributed throughout the myocardium after Percutaneous Coronary Intervention (PCI) and stenting and were retained for at least 24 h after myocardial ischemia with reperfusion (MI/R)
Summary
Cardiovascular disease is the leading cause of death worldwide, accounting for 31% of all deaths and the loss of nine million people annually (Virani et al, 2020). Of these deaths, about 50% are attributed to coronary heart disease (Smith et al, 2015). Primary PCI is the most common strategy for revascularization and preferred over fibrinolytic therapy for patients when time-totreatment delays are relatively short (
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
