Intravenous high mobility group box 1 fragment improves cardiac function, fibrosis, and coronary flow in porcine ischemic cardiomyopathy model.

Abstract

One of the regenerative medicine approaches for severe heart failure (HF) involves enhancing the inherent regenerative capacity, with mesenchymal stem cells (MSCs) being a crucial element. High mobility group box 1 (HMGB1) has been reported to promote the mobilization of MSCs from the bone marrow and contribute to tissue repair. We hypothesized that cardiac function would improve through this mechanism in a porcine ischemic cardiomyopathy (ICM) model and analyzed its effectiveness using various imaging modalities, histological analyses, and RT-PCR. Echocardiography revealed an increased left ventricular (LV) ejection fraction and reduced LV end-systolic volume. Cardiac magnetic resonance imaging with late gadolinium enhancement demonstrated improved regional LV strain and a smaller scarred myocardial zone. A pressure wire study in the coronary arteries showed enhanced coronary flow reserve and resistive reserve ratio. Histological analysis exhibited a smaller cardiomyocyte diameter, reduced fibrosis area, and an increased number of CD31-positive endothelial cells. RT-PCR analysis indicated elevated levels of pro-angiogenic, anti-fibrotic, and anti-inflammatory factors such as SDF1, HGF, FGF2, and TGFb3. These findings suggested that HMGB1 fragment activated a self-tissue repair pathway, leading to improved cardiac function. The less-invasive intravenous administration of the HMGB1 fragment highlights its potential as a regenerative therapy for severe HF.