Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Abstract

Purpose Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. Materials and methods Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. Results LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.

The Expression of Lipoprotein Receptors Is Increased in the Infarcted Area After Myocardial Infarction Induced in Rats With Cardiac Dysfunction

“…SR‐BI is expressed in several cell types relevant to inflammatory and proliferative processes, including monocytes, macrophages, dendritic cells, platelets, and neoplastic cells (Hoekstra, ; Wang et al, ; Yuan et al, ). The finding of increased expression of SR‐BI in the noninfarcted myocardial area was therefore expected, since all these cells are present in greater number in the post infarcted myocardium, as we previously documented (Maranhão et al, ).…”

Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

“…In a rat model of reperfused MI, cyclophosphamide administration attenuated leukocyte infiltration and reduced ventricular dysfunction (Zhu et al, ). Methotrexate treatment was also found to exert protective effects on the ischaemic and reperfused myocardium in both large animal (Asanuma et al, ) and rodent models (Maranhao et al, ). However, in a small clinical trial, methotrexate administration to patients with STEMI did not affect acute infarct size and worsened systolic dysfunction 3 months after the acute event (Moreira et al, ).…”

Effect of paeoniflorin on cardiac remodeling in chronic heart failure rats through the transforming growth factor β1/Smad signaling pathway

“…Effect of paeoniflorin on cardiac remodeling in chronic heart failure rats through the transforming growth factor β1/Smad signaling pathway role in the development of cardiac remodeling (3)(4)(5). Previous studies have found that methotrexate, rapamycin and triptolide can regulate inflammatory responses, alleviate cardiac fibrosis and improve cardiac function in rats (6)(7)(8). Therefore, more and more scholars all over the world began to explore the application value of anti-inflammatory and immunomodulation strategy in CHF.…”