Abstract
Toll-like receptors (TLRs) are essential receptors of the innate immune system, playing a significant role in cardiovascular diseases. TLR4, with the highest expression among TLRs in the heart, has been investigated extensively for its critical role in different myocardial inflammatory conditions. Studies suggest that inhibition of TLR4 signaling pathways reduces inflammatory responses and even prevents additional injuries to the already damaged myocardium. Recent research results have led to a hypothesis that there may be a relation between TLR4 expression and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in various inflammatory conditions, including cardiovascular diseases. AMPK, as a cellular energy sensor, has been reported to show anti-inflammatory effects in various models of inflammatory diseases. AMPK, in addition to its physiological acts in the heart, plays an essential role in myocardial ischemia and hypoxia by activating various energy production pathways. Herein we will discuss the role of TLR4 and AMPK in cardiovascular diseases and a possible relation between TLRs and AMPK as a novel therapeutic target. In our opinion, AMPK-related TLR modulators will find application in treating different immune-mediated inflammatory disorders, especially inflammatory cardiac diseases, and present an option that will be widely used in clinical practice in the future.
Highlights
Inflammation has long been associated with many diseases, including diabetes, cancer, arthritis, and cardiovascular complications
Some of the main molecular anti-inflammatory mechanisms of AMPK were reviewed by Salt and Palmer[81] in 2012 and shown in Figure 2, which include inhibition of cytokine-stimulated iNOS protein expression and inhibition of NF-kB signaling,[82] inhibition of MAPK pathways,[83] modulations t of reactive oxygen species synthesis,[84,85] inhibition of JAK-STAT signaling,[86] prevention of leukocyte infiltration,[87] regulation of cytokine synthesis[88] and regulation of lipid metabolism ip by maintaining fatty acid oxidation in macrophages to limit inflammation.[89] r AMPK and cardiovascular disease
Toll-like receptors (TLRs) and AMPK relation in reducing adipogenesis, adipose te inflammation, and promoting energy expenditure recently was confirmed in a mice model of obesity by modulating SIRT1 (Sirtuin 1, an enzyme function as intracellular regulatory proteins), TNF-α and IL-6 associated metabolic and inflammatory pathways.[109] p Despite numerous references to the anti-inflammatory role of AMPK, the pro-inflammatory impress of AMPK in TLR4 cascade was mentioned by Kim et al.[110] in 2012
Summary
Inflammation has long been associated with many diseases, including diabetes, cancer, arthritis, and cardiovascular complications.
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