TLR9 is essential for HMGB1-mediated post-myocardial infarction tissue repair through affecting apoptosis, cardiac healing, and angiogenesis

Abstract

The poor prognosis of patients with acute myocardial infarction is partially attributed to a large number of cardiomyocyte apoptosis, necrosis, limited cardiac healing and angiogenesis, and cardiac dysfunction. Immune cells dysfunction leads to nonhealing or poor healing of wounds after acute myocardial infarction. Toll-like receptor 9 (TLR9) as an essential part of the innate immune system plays a vital role in regulating cardiomyocyte survival and wound healing. During hypoxia, High Mobility Group Box 1 (HMGB1), as the typical damage-associated molecular patterns (DAMPs) or alarmin, is rapidly released extracellularly and translocates from the nucleus to bind with cytoplasmic TLR9. However, the mechanism by which TLR9 interacts with HMGB1 and regulates myocardial damage remains unclear. Our current study found that the survival rate of TLR9KO mice with a higher rate of cardiac rupture was significantly lower than that in WT mice after 28 days post-operation. The effect of TLR9 knockout on insufficient wound healing in experimental MI was caused by a diminished number of myofibroblast and defective matrix synthetic capability. Moreover, the increased myocardial apoptotic cells and decreased angiogenic capacity were found in TLR9 knockout mice after MI. The results showed contrary in Recombinant Human High Mobility Group Box 1 (rhHMGB1) treated WT mice and similarity after applying rhHMGB1 in TLR9KO mice. This study demonstrates that TLR9 is essential for the repair of infarcted myocardium and interaction of HMGB1 and TLR9 is involved in the survival of myocardial cells, wound healing, and angiogenesis after myocardial infarction.

PTX3 Predicts Myocardial Damage and Fibrosis in Duchenne Muscular Dystrophy

“…Recently, it was shown that TLR5 inhibition ameliorates cardiac fibrosis by modulating inflammation and tissues' remodeling (Liu et al, 2015). Other studies determined that HMGB1 blockade alleviates myocardial fibrosis (Wang et al, 2014), possibly interfering with the TLR2-HMGB1 ligand and cardiac autophagy (Wu et al, 2018;Liu et al, 2019). Consistent with these evidences, we demonstrated that mdx cardiac dysfunctions could be partly due to an inflammatory signaling pathway in which PTX3 is involved together with S100β, HMGB1, TLR5, and TLR9, with consequent increment of collagen deposition and fibrosis.…”

A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα

“…TLR7 deficiency suppresses the cardiac remodeling process induced by myocardial infarction 37 . TLR9 is essential in the pathology of the cardiac remodeling process postmyocardial infarction 38 . In our experiment, we observed an increased level of TLR4, and TLR7, and a decreased level of TLR9 expression in hypertrophic cardiomyocytes.…”

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

“…Recently, TLR9 also showed to contribute to the inflammatory response following MI in a mouse model through stimulation by HMGB-1 and mtDNA (12). However, a contrary report observed that TLR9-HMGB-1 was essential for survival of cells, wound healing and angiogenesis in a model with a longer follow-up (13). Experimental studies investigation the role of TLR5 were also performed and it is expressed in the hearts of mice, rats and humans (152).…”