Elevated Expression of TLR2 in Aging Hearts Exacerbates Cardiac Inflammatory Response and Adverse Remodeling Following Ischemia and Reperfusion Injury

Abstract

This study tested the hypothesis that Toll-like receptor 2 (TLR2) augments the inflammatory responses and adverse remodeling in aging hearts to exacerbate myocardial injury and cardiac dysfunction.MethodsOld (20-22 months old) and adult (4-6 months old) mice of C57BL/6 wild-type and TLR2 knockout (KO) were subjected to coronary artery ligation (30 minutes) and reperfusion (3 or 14 days). Left ventricle function was assessed using a pressure-volume microcatheter. Cardiac infarct size was determined by histology. Levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase 9 (MMP 9), and collagen I in non-ischemic myocardium were assessed by immunoblotting. Monocyte chemoattractant protein-1 (MCP-1), keratinocyte chemoattractant (KC), and interleukin-6 (IL-6) levels in ischemic and non-ischemic myocardium were measured by enzyme-linked immunosorbent assay (ELISA). TLR2 expression in the myocardium of untreated wild type mice was also measured by immunoblotting.ResultsHigher levels of MCP-1, KC, IL-6 were induced in both ischemic and non-ischemic myocardium of old wild type mice at day 3 and 14 following ischemia/reperfusion (I/R) than those of adult wild type mice. The hyper-inflammatory responses to I/R in aging hearts were associated with elevated levels of myocardial TLR2. TLR2 KO markedly down-regulated the expression of MCP-1, KC, IL-6, ICAM-1 and VCAM-1 in aging hearts at day 3 and 14 following I/R. The down-regulated inflammatory activity in aging TLR2 KO hearts was associated with attenuated production of MMP 9 and collagen I at day 14 and resulted in reduced infarct size and improved cardiac function.ConclusionElevated expression of myocardial TLR2 contributes to the mechanism by which aging exacerbates the inflammatory responses, adverse remodeling and cardiac dysfunction following myocardial I/R in aging.

Aging exacerbates cardiac dysfunction and mortality in sepsis through enhancing TLR2 activity

“…Our previous study found that the myocardium of old mice has higher level of TLR2 ( 13 ), and the present study confirmed this observation and identified elevated TLR2 levels in the liver and kidney. Based on these findings, we tested the hypothesis that elevated TLR2 levels augment inflammatory activity in sepsis and thereby results in worse cardiac dysfunction.…”

“…Although TLR signaling is essential for host defense, persistent activation of TLRs, particularly TLR2, and related signaling pathways during sepsis would result in dysregulated systemic inflammatory responses ( 12 ). We observed in a previous study that aging elevates myocardial TLR2 levels ( 13 ), indicating that elevated TLR2 activity in aging heart augments myocardial inflammatory responses to sepsis. The current study tested the hypothesis that TLR2 plays a critical role in mediating myocardial inflammatory responses and cardiac dysfunction in old septic mice.…”

“…Our previous study found that the myocardium of old mice has higher level of TLR2 and displays enhanced inflammatory response to ischemia ( 13 ). The present study found that old mice had higher TLR2 levels in the heart, liver and kidney ( Figure 3 ).…”

“…However, excessive activation of theTLR2 signaling pathway contributes to tissue damage, organ failure, and even mortality during sepsis. Previous studies have shown that aging is an independent predictor of mortality in sepsis ( 4 , 28 ), and elevated TLR2 activity in the aging heart exacerbates myocardial inflammatory activity ( 13 ). In the current study, we observed that TLR2 activity was greater in the hearts of old WT mice compared with young WT mice when using a specific TLR2 agonist, PAM3CSK4, to stimulate this innate immune receptor.…”

People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case–control study

“…In addition, anti-apoA1 IgG could directly promote the endothelial expression of ICAM-1 and VCAM-1. Although the present study did not investigate underlying molecular mechanisms, previous publications showed that ICAM-1 and VCAM-1 expression is TLR2/TLR4-dependent ( 39 – 41 ), suggesting that the same innate immune receptors could be involved in anti-apoA1 IgG-induced trans-endothelial migration of immunocompetent cells. The impact of ART on auto-antibodies is poorly documented; however, the observation in our study is in line with the findings of Marinho and colleagues ( 42 ), who showed that the anti-retroviral nevirapine (NVP) was able to lower the titres of anti-HDL auto-antibodies, which are closely related to anti-apoA1 antibodies.…”