Localized delivery of mechano-growth factor E-domain peptide via polymeric microstructures improves cardiac function following myocardial infarction

Abstract

The Insulin like growth factor-I isoform mechano-growth factor (MGF), is expressed in the heart following myocardial infarction and encodes a unique E-domain region. To examine E-domain function, we delivered a synthetic peptide corresponding to the unique E-domain region of the human MGF (IGF-1Ec) via peptide eluting polymeric microstructures to the heart. The microstructures were made of poly (ethylene glycol) dimethacrylate hydrogel and bioengineered to be the same size as an adult cardiac myocyte (100×15×15 μm) and with a stiffness of 20 kPa. Peptide eluting microrods and empty microrods were delivered via intramuscular injection following coronary artery ligation in mice. To examine the physiologic consequences, we assessed the impact of peptide delivery on cardiac function and cardiovascular hemodynamics using pressure-volume loops and gene expression by quantitative RT-PCR. A significant decline in both systolic and diastolic function accompanied by pathologic hypertrophy occurred by 2 weeks which decompensated further by 10 weeks post-infarct in the untreated groups. Delivery of the E-domain peptide eluting microrods decreased mortality, ameliorated the decline in hemodynamics, and delayed decompensation. This was associated with the inhibition of pathologic hypertrophy despite increasing vascular impedance. Delivery of the empty microrods had limited effects on hemodynamics and while pathologic hypertrophy persisted there was a decrease in ventricular stiffness. Our data show that cardiac restricted administration of the MGF E-domain peptide using polymeric microstructures may be used to prevent adverse remodeling of the heart and improve function following myocardial infarction.

The human Ec peptide: the active core of a progression growth factor with species-specific mode of action

“…Bearing in mind the above, our data suggesting an overexpression of IGF-1Ec by injured tissues, such as by the surrounding tissues in prostate cancer, is reminiscent of the preferential expression of IGF-1Ec post-skeletal muscle damage and that of the myocardium during the post-infarction period. [30][31][32][33][34][35][36] Interestingly, species-specific differences of hEc and mE actions may point to a possible different mode of actions at the receptor level. It has been reported that mE requires IGF-1R for its bioactivity, 36 while hEc appears to act in an IGF-1R independent manner.…”

“…It has been reported that mE requires IGF-1R for its bioactivity, 36 while hEc appears to act in an IGF-1R independent manner. 15,20,33 Thus, the residue rat position 23 of hEc is probably crucial for hEc receptor recognition.…”

Lipid signaling affects primary fibroblast collective migration and anchorage in response to stiffness and microtopography

“…Neomycin delivered locally from microporous microrods might be advantageous in clinical use. MGF eluted over several days from PEGDMA microrods (Doroudian et al, 2014) improved cardiac function after ischemia injury (Peña, Pinney, Ayala, Desai, & Goldspink, 2015). PEGDMA microrods were loaded with high concentrations of neomycin and maintain release over 12 hr.…”

Biomimetic particles as therapeutics

“…As an example, hydrogel microrods can deliver an insulin like growth factor mimicking peptide to prevent unwanted cardiac remodeling and enhance survival in a post myocardial infarction mouse model [64]. Additionally, for neural regeneration, PLGA nanoparticles have been shown to deliver leukemia inhibitory factor to support the growth of dopaminergic cells for the regeneration of lost tissue observed in Parkinson's disease [65].…”