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Published on: June 14, 2015
Cardiac Homing Peptide-Functionalized Polymeric Nanoparticles Suppressing SHP1 Alleviate Acute Myocardial Infarction
Qi Pan1, Guihao Chen1, Xiaoli Zhuang2
1State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Insights
A novel nanoparticle system delivering a SHP1 inhibitor enhances efferocytosis in acute myocardial infarction (AMI) models. This promotes cardiac repair by clearing apoptotic cells and reducing inflammation, improving heart function and reducing fibrosis.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanomedicine
Background:
- Acute myocardial infarction (AMI) is a significant global health issue.
- Upregulated CD47 on apoptotic cardiomyocytes inhibits efferocytosis via the SIRPα/SHP1 axis, causing inflammation and impairing reparative M2 macrophage polarization.
- Systemic therapies targeting this axis face challenges due to potential adverse effects like fibrosis and immunosuppression.
Purpose of the Study:
- To develop a novel nanoparticle system for targeted delivery of a SHP1 inhibitor to enhance efferocytosis in AMI.
- To assess the pro-efferocytic, anti-inflammatory, and cardioprotective effects of the developed nanosystem in vitro and in vivo.
- To overcome limitations of systemic interventions by creating a targeted nanomedicine for cardiovascular disease treatment.
Main Methods:
- A poly(lactic-co-glycolic acid)@Polydopamine (PLGA@PDA) nanoparticle system (NP-TPI1) was engineered to deliver the SHP1 inhibitor TPI1.
- The nanoparticles were modified with a cardiac homing peptide (CHP) for targeted delivery to the heart (NP-TPI1/P).
- The efficacy of NP-TPI1/P was evaluated in Raw264.7 cells and a mouse AMI model, assessing efferocytosis, inflammation, cardiac function, and fibrosis.
Main Results:
- The ROS and low pH-responsive NP-TPI1/P effectively inhibited SHP1 phosphorylation, restoring efferocytosis of apoptotic cardiomyocytes.
- Treatment promoted M2 macrophage polarization and reduced secondary inflammatory responses post-AMI.
- NP-TPI1/P demonstrated enhanced targeting of infarcted lesions, leading to significantly improved cardiac performance (LVEF) and reduced cardiac fibrosis in AMI mice.
Conclusions:
- This study presents a novel dual-purpose nanomedicine for post-myocardial infarction treatment.
- The engineered nanoparticles effectively enhance efferocytosis and exert anti-inflammatory and cardioprotective effects.
- This approach holds significant potential for the clinical translation of efferocytosis-based therapies in cardiovascular diseases.
Purpose:
Acute myocardial infarction (AMI) is a major global health concern worldwide. The upregulation of the CD47 on apoptotic cardiomyocytes acts as a "don't-eat-me" signal, inhibiting the clearance of apoptotic cells by macrophages (a process known as efferocytosis) via the Signal Regulatory Protein α (SIRPα)/ SH2 Domain-Containing Phosphatase 1 (SHP1) axis, leading to secondary inflammatory activation. Additionally, impairment of this process can result in insufficient macrophage polarization towards the reparative M2 phenotype. Systemic interventions targeting this axis are constrained by potential adverse effects such as promoting fibrosis, suppressing immunity, and interfering with the protective function of the axis to avoid phagocytosis of normal cells.
Methods:
In this study, a poly(lactic-co-glycolic acid)@Polydopamine (PLGA@PDA) nanoparticle system was developed to deliver the SHP1 inhibitor TPI1 (NP-TPI1). The nanoparticle was modified with cardiac homing peptide (CHP) to enable heart homing (NP-TPI1/P). Raw264.7 cells and mouse AMI models were utilized to assess the pro-efferocytic, anti-inflammatory, and cardioprotective effects of the novel nanosystem.
Results:
This novel nanoparticle, which is responsive to ROS and low pH, effectively inhibited SHP1 phosphorylation both in vitro and in vivo, thereby restoring timely clearance of apoptotic cells by macrophages. It also promotes M2 polarization and reduces the secondary inflammatory response. These engineered nanoparticles exhibited an enhanced capability to target infarcted lesions, and AMI mice treated with CHP-modified TPI1-loaded nanoparticles showed significantly improved cardiac performance (left ventricular ejection fraction [LVEF] of NP-TPI1/P vs PBS, 49.42±1.88 vs 31.61±2.30 [%] at day 21 post-AMI) and reduced fibrotic area (NP-TPI1/P vs PBS, 11.60±1.60 vs 25.48±1.98 [% of left ventricular]).
Conclusion:
This study provides new insights into the development of novel, dual-purpose nanomedicines for post-myocardial infarction, and holds significant potential for the clinical translation of efferocytosis in cardiovascular diseases.
