IL-13 Derived Type 2 Innate Lymphocytes Ameliorates Cardiomyocyte Apoptosis Through STAT3 Signaling Pathway.

The involvement of cardiomyopathy during sepsis means higher mortality and prolonged length of hospital stay. Many efforts have been made to alleviate the apoptosis of cardiomyocytes in sepsis. The huge potential of IL-13 in tissue repair has attracted increasing attention. In the present study, we used LPS-treated mice or primary cardiomyocytes as a sepsis model to explore the anti-apoptotic ability of IL-13. It was found that an increased level of exogenous IL-13 was beneficial to the recovery of heart function in sepsis, and this anti-apoptotic effect of IL-13 was probably through enhancing the phosphorylation of STAT3 Ser727. In addition, we identified that the heart protective effect of IL-13 was associated with type 2 innate lymphocytes (ILC2). All these findings may provide a potential promising treatment for sepsis-induced cardiomyopathy.

IL-13 Alleviates Cardiomyocyte Apoptosis by Improving Fatty Acid Oxidation in Mitochondria.

Sepsis-induced cardiac injury (SIC) is one of the most common complications in the intensive care unit (ICU) with high morbidity and mortality. Mitochondrial dysfunction is one of the main reasons for SIC, and Interleukin-13 (IL-13) is a master regulator of mitochondria biogenesis. The aim of the present study was to investigate the role of IL-13 in SIC and explore the underlying mechanism. It was found that reactive oxygen species (ROS) production and apoptosis were significantly increased in lipopolysaccharide (LPS)-stimulated primary cardiomyocytes, which was accompanied with obvious mitochondria dysfunction. The results of RNA-sequencing (RNA-seq), mitochondrial membrane potential, fatty acid uptake and oxidation rate suggested that treatment with IL-13 could restore the function and morphology of mitochondria, indicating that it played an important role in protecting septic cardiomyocytes. These findings demonstrated that IL-13 alleviated sepsis-induced cardiac inflammation and apoptosis by improving mitochondrial fatty acid uptake and oxidation, suggesting that IL-13 may prove to be a potential promising target for SIC treatment.

Engineered Biomimetic Nanoplatform Protects the Myocardium Against Ischemia/Reperfusion Injury by Inhibiting Pyroptosis.

Protection of cardiomyocytes against oxidative stress is vital to alleviate myocardial ischemia/reperfusion injury (MI/RI). However, antioxidative treatment is hampered by the lack of safe and effective therapeutics. Polydopamine (PDA), as a biodegradable class of nanomaterial with excellent antioxidant properties, has shown great potential in treating MI/RI. To achieve site-specific antioxidative efficacy, we established a PDA-based biomimetic nanoplatform (PDA@M), which consisted of a polydopamine core and a macrophage membrane shell to form a shell-core structure. By inheriting the inherent migration capability of macrophages, PDA@M was able to target the infarcted myocardium and exert an antioxidative effect to protect the myocardium. The results demonstrated that the accumulation of the membrane-wrapped nanoparticles (NPs) in the infarcted myocardium was greatly increased as compared with PDA alone, which effectively relieved the MI/RI-induced oxidative stress. PDA@M largely decreased the infarct size and improved the cardiac function post-MI/RI. Our study revealed that PDA@M could inhibit cell pyroptosis by suppressing the NLRP3/caspase-1 pathway, which is known to play a significant role in the antioxidant signaling pathway. In summary, PDA@M can target the infarcted myocardium and exert antioxidative and antipyroptosis functions to protect the myocardium against MI/RI-induced oxidative stress, suggesting that it may prove to be a potential therapeutic agent for MI/RI.

A Novel Anti-Coagulative Nanocomplex in Delivering miRNA-1 Inhibitor Against Microvascular Obstruction of Myocardial Infarction.

Great progress has been made in miRNA nanodelivery for the treatment of myocardial infarction (MI). However, miRNA nanodelivery within the infarct is impeded by microvascular obstruction as a local circulatory disorder caused by microthrombus formation in microvessels. Knowing that low molecular weight heparin (LMWH) can effectively prevent microthrombus formation in microcirculation, it is hypothesized whether surface modification of the nanocarrier with LMWH can overcome microvascular obstruction in the infarct area for better miRNA delivery. Herein, a novel nanocomlex consisting of dendrigraft poly-l-lysine (DGL)-loaded miR-1 inhibitor as the core to decrease apoptosis of cardiomyocytes and LMWH as the shell to overcome microvascular obstruction of the infarct area is developed. The results show that this anti-coagulative nanocomlex is able to reduce microthrombus formation in microvessels and inhibit blood-coagulation factor Xa, thereby overcoming microvascular obstruction in the infarct area. In addition, it further enhances the uptake of miR-1 inhibitor within the infarct and decreases myocardiocyte apoptosis, thus improving the cardiac function and attenuating the myocardial fibrosis. In conclusion, modification of DGL-loaded miR-1 inhibitor with LMWH helps overcome microvascular obstruction in delivering the drug to the infarct area, thus providing a promising therapeutic strategy for achieving a better therapeutic outcome of MI.

PCSK9 Hapten Multicopy Displayed onto Carrier Protein Nanoparticle: An Antiatherosclerosis Vaccine.

In recent years, various vaccination strategies have shed new light on the treatment of atherosclerosis. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a hot target in the development of antiatherosclerosis vaccine. However, the efficacy of conventional PCSK9 is largely limited by poor immunogenicity and low hapten density. Therefore, we hypothesized whether a nanostructure synthesized by self-assembled carrier protein accompanied by multicopy hapten display could improve the efficacy of vaccine. In this study, bovine serum albumin (BSA) was self-assembled into sub-100 nm nanoparticles via an intermolecular disulfide network as the inner core. Then, sequences of PCSK9 were conjugated onto the surface of nanoparticles by "click" chemistry to consequently form an orderly structured of nanovaccine with repetitive hapten display. Compared with conventional PCSK9 peptide vaccine, our immunization study demonstrated that the PCSK9 multicopy display nanovaccine (PMCDN) was able to induce higher titers of PCSK9 antibody and more efficient lymph node drainage and improve endocytosis by antigen presenting cells.