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Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist; it has anti-sympathetic, sedative and analgesic effects. Studies have demonstrated that DEX can inhibit the release of inflammatory factors and suppress the oxidative stress response to protect organs (7-9). With regards to RIRI, DEX has been revealed to alleviate ischemia-reperfusion-induced RIRI in both animal and human experiments, but its dose-response relationship and underlying mechanism are still unclear (8). Moreover, 4-phenylbutyric acid (4-PBA) is a low molecular weight fatty acid (10). A number of studies have confirmed that 4-PBA can be used as a molecular chaperone to reverse the incorrect displacement or incorrect aggregation of protein molecules to form a normal spatial structure (11,12). This decreases the overload of endoplasmic reticulum stress (ERS), suppresses the signal induction of ERS and alleviates the tissue damage caused by ERS (10). Furthermore, 4-PBA decreases hepatocyte apoptosis in hepatic ischemia-reperfusion injury and alleviates cerebral and spinal cord ischemic injury (13). However, the mechanism by which 4-PBA exerts its therapeutic effect on RIRI is largely unknown.
There are limitations to the present study. For example, the renal function of mice was not assessed using hematoxylin-eosin or Periodic acid-Schiff staining to detect pathological changes in the kidney, and the ERS was addressed using only two indicators, eIF2α and GRP78. In further studies, more indicators and parameters, including pathological examination, should be applied for an improved understanding of changes in renal function following treatment.
Obesity is a global epidemic1 and is associated with increased risk of developing cardiovascular diseases2. Various aspects of cardiac tissue remodelling are clearly linked to obesity and include cardiac fibrosis and cardiomyocyte hypertrophy3,4. Although the pathophysiology of obesity-related cardiac damage is complex and multifaceted, inflammation is believed to be crucial5,6. It is also known that free fatty acid (FFA) levels are increased in obese subjects7,8. Elevated levels of FFAs are independently associated with greater risks of cardiovascular events9,10,11. Among circulating FFAs, saturated fatty acid (SFA) palmitate (C16:0) is one of the most abundant12 and is increased in obese children and adolescents13. Studies have also established that SFAs activate inflammatory and innate immune responses14,15,16,17,18. We19 and others20,21 found that palmitic acid (PA) induces an inflammatory phenotype in cardiomyocytes. This inflammatory activity is characterized by increased production of pro-inflammatory cytokines and oxidants, leading to cellular hypertrophy and apoptosis. The findings indicate that elevated levels of PA and likely other SFAs can contribute significantly to cardiac damage.
Toll-like receptor 4 (TLR4) is an essential modulator of innate immunity, and links innate immunity and metabolic disorders including obesity14,16,22,23. The signalling mechanism engaged by SFAs appears to be through TLR4, triggering acute and chronic inflammation14,15,16,22,24,25. Studies have shown that a SFA- but not unsaturated fatty acid-rich diet induces leptin resistance, TLR4 activation and endoplasmic reticulum stress26. Furthermore, TLR4 blockade suppresses PA-induced cytokine production22. To date, it remains an open question as to how SFAs (as well as other metabolic factors) activate TLR4-dependent innate immune responses.
How to cite this article: Wang, Y. et al. Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat. Commun. 8, 13997 doi: 10.1038/ncomms13997 (2017). 2b1af7f3a8