Abstract
Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload-induced heart failure in mice. When administered before the operation andchronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.
Highlights
Isolated cardiomyocytes were stimulated by a TLR9 ligand (e.g., ODN1668), a TLR4 ligand (e.g., LPS), or a TLR7 ligand in the presence of increasing concentrations of E6446 [11,12]
The present study showed that E6446 prevents the development of pressure overload–induced heart failure when administered before the cardiac event and suppresses the progression of heart failure when started after cardiac dysfunction manifested
E6446 prevents cellular events activated by TLR9, exerting broader inhibitory effects on inflammatory cytokine production, and the treatment of heart failure with the inhibitor has an advantage over the therapy neutralizing only 1 cytokine
Summary
Adult cardiomyocytes were isolated from 10- to 12-week-old C57BL/6J male mice (CLEA Japan, Inc., Tokyo, Japan) by using a Langendorff system and were cultured [7]. Total ribonucleic acid (RNA) was extracted from the left ventricle or cultured cardiomyocytes by using the TRIzol reagent (Thermo Fisher Scientific, Waltham, Massachusetts) and reverse transcribed by using TaqMan Reverse Transcription Reagents (Thermo Fisher Scientific) [7]. LVDd, mm LVDs, mm LVFS, % IVSd, mm LVPWd, mm Heart rate, beats/min LV mass, mg. The echocardiographic parameters of the mice were obtained 2 weeks after the operation. Values are mean Æ SE. *p < 0.05 vs. baseline
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
