Type I collagen-targeted liposome delivery of Serca2a modulates myocardium calcium homeostasis and reduces cardiac fibrosis induced by myocardial infarction.

ABSTRACT

Fibrotic scarring and impaired myocardial calcium homeostasis serve as the two main factors in the pathology of heart failure following myocardial infarction (MI), leading to poor prognosis and death in patients. Serca2a is a target of interest in gene therapy for MI-induced heart failure via the regulation of intracellular calcium homeostasis and, subsequently, enhancing myocardial contractility. A recent study also reported that Serca2a ameliorates pulmonary fibrosis by blocking nuclear factor kB (NF-kB)/interleukin-6 (IL-6)-induced (SMAD)/TGF-ß signaling activation, while the effect in MI-induced myocardial fibrosis remains to be addressed. Here, we loaded Serca2a plasmids into type 1 collagen-targeting nanoparticles to synthesize the GKWHCTTKFPHHYCLY-Serca2a-Liposome (GSL-NPs) for targeted treatment of myocardial infarction. We showed that GSL-NPs were effectively targeted in the scar area in MI-induced mice within tail-vein delivery for 48 h. Treatment with GSL-NPs improved cardiac functions and shrank fibrotic scars after MI in mice by up-regulating Serca2a. In cardiac fibroblasts, GSL-NPs alleviated hypoxia-induced fibrotic progression partly by inhibiting NF-kB activation. Furthermore, treatment with GSL-NPs protected cardiomyocyte calcium homeostasis and enhanced myocardial contractility during hypoxia. Together, we demonstrate that type I collagen-targeted liposome delivery of Serca2a may benefit patients with myocardial infarction by inhibiting fibrotic scarring as well as modulation of calcium homeostasis.