There are limitations in the current classification of danger associated molecular patterns (DAMP) receptors. To overcome these limitations, we propose a new paradigm by using endogenous metabolites lysophospholipids (LPLs) as a prototype. By utilizing a data mining method we pioneered, we made the following findings: 1) Endogenous metabolites such as LPLs at basal level have physiological functions; 2) under sterile inflammation, expression of some LPLs are elevated. These LPLs act as conditional DAMPs or anti-inflammatory homeostasis-associated molecular pattern molecules (HAMPs) for regulating the progression of inflammation or inhibition of inflammation, respectively; 3) receptors for conditional DAMPs and HAMPs are differentially expressed in human and mouse tissues; and 4) complex signaling mechanism exists between pro-inflammatory mediators and classical DAMPs that regulate the expression of conditional DAMPs and HAMPs. This novel insight will facilitate identification of novel conditional DAMPs and HAMPs, thus promote development of new therapeutic targets to treat inflammatory disorders.

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Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.

Background/Aims: Atherosclerosis is a chronic inflammatory disease. Intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) play important roles in inflammatory processes. P38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling regulate ICAM-1, VCAM-1, and MCP-1 expression. Angiotensin (Ang) II upregulates ICAM-1, VCAM-1, and MCP-1 expression through the P38 MAPK and NF-κB pathways. Ang-(1-7) may oppose the actions of Ang II. We investigated whether Ang-(1-7) prevents Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression in human umbilical vein endothelial cells (HUVECs). Methods: ICAM-1, VCAM-1, and MCP-1 expression was estimated by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA); P38, NF-κB, and p-IκB-a expression was estimated by western blotting. Results: Ang-(1-7) inhibited Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression and secretion in HUVECs. Ang II sharply increased P38 MAPK phosphorylation, which was inhibited by pretreatment with Ang-(1-7). Moreover, Ang-(1-7) significantly inhibited Ang II-induced IκB-a phosphorylation and NF-κB P65 nuclear translocation. The MAS receptor antagonist A-779 abolished the suppressive effects of Ang-(1-7). Conclusion: Ang-(1-7) attenuates Ang II-induced ICAM-1, VCAM-1, and MCP-1 expression via the MAs receptor by suppressing the P38 and NF-κB pathways in HUVECs. Ang-(1-7) might delay the progression of inflammatory diseases, including atherosclerosis.

Background Insulin resistance (IR), endothelial dysfunction, inflammation, glucose and lipid metabolism disorders, and thrombosis are believed involved in coronary heart disease (CHD) and non-alcoholic fatty liver disease (NAFLD). Triglyceride-glucose (TyG) index, a new IR indicator, is correlated with NAFLD occurrence and severity, but its relationship with CHD risk remains unclear. This study investigated the correlation between TyG index and CHD risk among NAFLD patients. Methods This cross-sectional study included 424 patients with NAFLD and chest pain in the Department of Cardiology, The Second Hospital of Shanxi Medical University, from January 2021 to December 2021. The TyG index was calculated and coronary angiography performed. All individuals were divided into NAFLD + CHD and NAFLD groups and then by TyG index level. The t-test, Mann–Whitney U-test, or one-way analysis of variance compared differences in continuous variables, while the chi-square test or Fisher’s exact test compared differences in categorical variables. Logistic regression analysis determined the independent protective or hazardous factors of NAFLD with CHD. The receiver operating characteristic curve evaluated the ability of different TyG index rule-in thresholds to predict CHD. The relationship between Gensini score and TyG index was evaluated using linear correlation and multiple linear regression. Results CHD was detected in 255 of 424 patients. Compared to NAFLD group, multivariate logistic regression showed that TyG index was a risk factor for CHD among NAFLD patients after adjustment for age, sex, hypertension, and diabetes mellitus with the highest odds ratio (OR, 2.519; 95% CI, 1.559–4.069; P < 0.001). TG, low-density lipoprotein cholesterol, FBG and TYG–body mass index were also risk factors for CHD among NAFLD patients. High-density lipoprotein cholesterol level was a protective factor for CHD events in patients with NAFLD. In an in-depth analysis, multivariate logistic regression analysis showed that each 1-unit increase in TyG index was associated with a 2.06-fold increased risk of CHD (OR, 2.06; 95% CI, 1.16–3.65; P = 0.013). The multifactor linear regression analysis showed each 0.1-unit increase in TyG in the NAFLD-CHD group was associated with a 2.44 increase in Gensini score (β = 2.44; 95% CI, 0.97–3.91; P = 0.002). Conclusions The TyG index was positively correlated with CHD risk in NAFLD patients and reflected coronary atherosclerosis severity.

Macroautophagy/autophagy is increasingly recognized as an important regulator of myocardial ischemia-reperfusion (MI-R) injury. However, whether and how diabetes may alter autophagy in response to MI-R remains unknown. Deficiency of ADIPOQ, a cardioprotective molecule, markedly increases MI-R injury. However, the role of diabetic hypoadiponectinemia in cardiac autophagy alteration after MI-R is unclear. Utilizing normal control (NC), high-fat-diet-induced diabetes, and Adipoq knockout (adipoq) mice, we demonstrated that autophagosome formation was modestly inhibited and autophagosome clearance was markedly impaired in the diabetic heart subjected to MI-R. adipoq largely reproduced the phenotypic alterations observed in the ischemic-reperfused diabetic heart. Treatment of diabetic and adipoq mice with AdipoRon, a novel ADIPOR (adiponectin receptor) agonist, stimulated autophagosome formation, markedly increased autophagosome clearance, reduced infarct size, and improved cardiac function (P < 0.01 vs vehicle). Mechanistically, AdipoRon caused significant phosphorylation of AMPK-BECN1 (Ser93/Thr119)-class III PtdIns3K (Ser164) and enhanced lysosome protein LAMP2 expression both in vivo and in isolated adult cardiomyocytes. Pharmacological AMPK inhibition or genetic Prkaa2 mutation abolished AdipoRon-induced BECN1 (Ser93/Thr119)-PtdIns3K (Ser164) phosphorylation and AdipoRon-stimulated autophagosome formation. However, AdipoRon-induced LAMP2 expression, AdipoRon-stimulated autophagosome clearance, and AdipoRon-suppressed superoxide generation were not affected by AMPK inhibition. Treatment with MnTMPyP (a superoxide scavenger) increased LAMP2 expression and stimulated autophagosome clearance in simulated ischemic-reperfused cardiomyocytes. However, no additive effect between AdipoRon and MnTMPyP was observed. Collectively, these results demonstrate that hypoadiponectinemia impairs autophagic flux, contributing to enhanced MI-R injury in the diabetic state. ADIPOR activation restores AMPK-mediated autophagosome formation and antioxidant-mediated autophagosome clearance, representing a novel intervention effective against MI-R injury in diabetic conditions.

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