Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver

Abstract

Ischemic heart disease is a leading cause of death worldwide. After the onset of myocardial infarction, many pathological changes take place and progress the disease towards heart failure. Pathologies such as ischemia, inflammation, cardiomyocyte death, ventricular remodeling and dilation, and interstitial fibrosis, develop and involve the signaling of many proteins. Proteins can play important roles in limiting or countering pathological changes after infarction. However, they typically have short half-lives in vivo in their free form and can benefit from the advantages offered by controlled release systems to overcome their challenges. The controlled delivery of an optimal combination of proteins per their physiologic spatiotemporal cues to the infarcted myocardium holds great potential to repair and regenerate the heart. The effectiveness of therapeutic interventions depends on the elucidation of the molecular mechanisms of the cargo proteins and the spatiotemporal control of their release. It is likely that multiple proteins will provide a more comprehensive and functional recovery of the heart in a controlled release strategy.

Keywords: Biomaterials; Controlled release; Delivery systems; Extracellular matrix; Myocardial infarction; Protein therapy.

Fig. 1

Myocardial infarction (MI) causes severe damage and adverse remodeling in the left ventricle (LV) myocardium, leading over time to LV wall thinning and dilation and ultimately progressing to contractile dysfunction and heart failure.

Fig. 2

Schematic of a protein therapy design. An effective therapy requires the elucidation of the pathological changes after MI, leading to the identification of involved proteins. It is also essential to develop a proper delivery technology that can encapsulate proteins of interest and deliver them in a physiologic manner. The optimized strategy can potentially counter or reverse the pathological progression and trigger the repair and regeneration mechanisms in the heart.

Fig. 3

Fate of angiogenesis induced by combination or single protein therapies. A combination therapy that employs proteins involved in triggering angiogenesis (i.e. VEGF, FGF-2) in combination with proteins involved in stabilizing new blood vessels by pericytes (i.e. PDGF, ANG1), is more likely to induce a robust angiogenesis process forming mature and stable vasculature. Single protein therapies might lead to a transient angiogenesis process with new blood vessels prone to regression due to lack of stability and maturity provided by pericytes.

Fig. 4

Ischemia, reactive oxygen species (ROS), and inflammation can trigger pro-apoptotic protein signaling (Bax, Bak) and inhibit anti-apoptotic protein signaling (Bcl-2, Bcl-x_L) within cardiomyocytes leading to release of cytochrome c and activation of caspases causing apoptosis. Pro-survival proteins that bind to their respective receptors on the myocyte surface can trigger PI3K/Akt and Ras-Raf-MEK-ERK pathways anti-apoptotic molecular pathways to prevent cell death.

Fig. 5

The myocardial extracellular matrix (ECM) serves as the base that connects cardiomyocytes, provides structural stability, and enables the transmission of chemical signals and contractile forces. The ECM contains structural proteins such as collagen and elastin, proteoglycans such as heparan sulfate, and adhesive glycoproteins such as fibronection and laminin. The ECM composition and orientation are strictly regulated in a healthy myocardium mainly by matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). TIMPs can help reduce early ECM degradation after MI alongside GFs involved in promoting cell survival, cardiomyogenesis, and angiogenesis.

Fig. 6

Repair and regeneration of the infarcted myocardium can be driven by delivery of proteins that address MI pathologies. To treat MI, a therapy needs to promote ECM homeostasis, stem cell homing, cardiomyogenesis, and angiogenesis, and prevent excessive inflammation, calcium imbalance, cardiomyocyte death, and fibrosis. Processes needed to be promoted or prevented after MI can have temporal differences. Some such as ECM homeostasis and calcium balance need to happen early on, while others such as fibrosis prevention should happen later. Injecting a protein delivery system carrying specific proteins of interest and delivering them per their physiologic cues offers the potential to trigger repair and regeneration signaling cascades leading to the restoration of a functional myocardium.

Fig. 7

Desirable properties of an effective protein delivery system. Practically, it may be difficult to satisfy all of the desirable properties and a balance has to be made based on cost and resources.

Fig. 8

Commonly used and developed drug delivery systems include hydrogels, nano/micro particles, coacervates, self-assembled nanofibers, porous scaffolds, and liposomes. The structural, mechanical, and chemical properties of these systems can be modified to control the release kinetics of cargo.

Fig. 9

Different release profiles can be attained by different controlled release systems. The rate and style of release over a certain period can be controlled by changing the design and chemical and mechanical properties of the delivery vehicle.

Fig. 10

(A) A coacervate can be self-assembled by mixing PEAD and heparin. Embedding VEGF in a fibrin gel and PDGF in a coacervate that is distributed in the same gel leads to a (B) sequential release of VEGF followed by PDGF. (C) Sequential delivery of VEGF and PDGF significantly improves cardiac function in rats compared to saline, empty delivery vehicle, and free proteins. (D) Hematoxylin and eosin (H&E) staining shows significant damage of heart morphology, dilation, wall thinning, scar expansion, and granulated tissue in saline control compared to significant reduction of damage due to sequential delivery after MI.