Timely myocardial reperfusion is essential for restoring blood flow to post-ischemic tissue, thereby reducing cardiac injury and limiting infarct size. However, this process can paradoxically result in additional, irreversible myocardial damage, known as myocardial ischemia–reperfusion injury (MIRI). The goal of this review is to explore the role of specialized pro-resolving mediators (SPMs) in atherosclerosis and MIRI, and to assess the therapeutic potential of targeting inflammation resolution in these cardiovascular conditions.
This review summarizes current preclinical and clinical evidence on the involvement of SPMs in the pathogenesis of atherosclerosis and MIRI, acknowledging that several cellular and molecular aspects of their mechanisms of action remain to be fully elucidated.
MIRI is a complex phenomenon in which inflammation, initially triggered during ischemia and further amplified upon reperfusion, plays a central role in its pathogenesis. Various cellular and molecular players mediate the initial pro-inflammatory response and the subsequent anti-inflammatory reparative phase following acute myocardial infarction (AMI), contributing both to ischemia- and reperfusion-induced damage as well as to the healing process. SPMs have emerged as key endogenous immunoresolvents with potent anti-inflammatory, antioxidant, and pro-resolving properties that contribute to limit excessive acute inflammation and promote tissue repair. While dysregulated SPM-related signaling has been linked to various cardiovascular diseases (CVD), their precise role in AMI and MIRI remains incompletely understood.
Targeting inflammation resolution may represent a promising therapeutic strategy for mitigating atheroprogression and addressing a complex condition such as MIRI.
Patients with chronic kidney disease (CKD) are at increased cardiovascular risk. Since neutrophils play a central role in atherosclerosis and cardiovascular disease, this study analyzed neutrophil function in CKD patients.
A systematic review of neutrophil function in CKD patients compared to controls was performed according to PRISMA guidelines by searching PubMed and the Web of Science. A meta-analysis summarized the production of reactive oxygen species (ROS) in CKD patients on dialysis in Forest plots. Influencer outlier analyses evaluated risk of bias.
Overall, 92 studies were included, of which 18 in the meta-analysis. Although study heterogeneity was high, the systematic review identified primarily reduced phagocytosis capacity but increased neutrophil degranulation and basal ROS production in neutrophils from CKD patients on hemodialysis compared to controls. Phagocytosis and basal ROS production were mainly unaltered in non-dialysis dependent CKD patients and CKD patients on peritoneal dialysis. The meta-analysis confirmed increased ROS generation in basal conditions predominantly in CKD patients on hemodialysis (Hedges g = 1.20, 95% CI: [0.32; 2.09]), with an insufficient study number for a clear comparison to CKD patients on peritoneal dialysis. However, upon neutrophil stimulation with sterile inflammatory triggers, ROS production was also increased in neutrophils from patients on peritoneal dialysis (Hedges g = 0.89, 95% CI: [0.34; 1.43]).
Increased degranulation and basal ROS formation were observed in neutrophils of CKD patients on hemodialysis, which could contribute to their increased cardiovascular risk. Future studies should compare neutrophil activity in patients of different CKD stages and comorbidities also in relation to cardiovascular outcomes.
Rivera-Gonzalez O, Mills MF, Konadu BD, Wilson NA, Murphy HA, Newberry MK, Hyndman KA, Garrett MR, Webb DJ, Speed JS. Adipocyte endothelin B receptor activation inhibits adiponectin production and causes insulin resistance in obese mice. Acta Physiol (Oxf). 2024 Oct;240(10):e14214. doi: 10.1111/apha.14214. Epub 2024 Aug 3. PMID: 39096077; PMCID: PMC11421981.
In the section “Funding Information,” the incorrect award number was inserted attributing credit to P20GM104357. We would like to correct this by replacing “P20GM104357” with “P30GM149404.”
We apologize for this error.
The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti-hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5′-adenosine monophosphate (AMP)-dependent inhibition of fructose-1,6-bisphosphatase 1 (FBP1) to the anti-hyperglycaemic action of salicylate.
We studied AMP-insensitive FBP1 G27P knockin (KI) mice through a variety of cellular approaches, including proteomics, Seahorse metabolic analysis, glucose production, and other assays, in addition to a detailed assessment of metabolic responses in vivo.
Compared with wild-type littermates, AMP-insensitive FBP1 KI mice were resistant to the effects of the drug on body weight, glucose tolerance, pyruvate disposal, liver lipid content and hepatic glucose production. Compared with wild-type, KI hepatocytes exhibited baseline differences in glycolytic, TCA cycle and fatty acid oxidation enzyme levels, potentially linking gluconeogenic dysregulation and its reversal to non-carbohydrate fuel management.
Collectively, our data highlight a novel mechanism of action for the effects of salicylate on glycaemia and weight gain, which depends on AMP-mediated allosteric inhibition of FBP1.
Microglia exhibit innate immune memory, altering their responses to subsequent challenges. Consumption of high-fat diet (HFD) triggers innate immune responses, but the characteristics of HFD-induced microglial priming remain unclear. We aim to investigate how HFD-induced microglial priming, followed by a lipopolysaccharide (LPS) challenge, affects brain functions.
Male Wistar rats were divided into control, unprimed, and primed groups. The primed groups received either a single LPS injection (0.5 mg/kg, intraperitoneally) or HFD consumption for 4–8 weeks. Following the priming phase, all rats (except controls) were subjected to an LPS challenge with a 4- or 8-week interval. After 24 h of LPS challenge, cognition, anxiety-, and depressive-like behaviors were assessed. The brain and hippocampus were collected for further analysis.
Both LPS- and 4-week HFD-primed groups, followed by LPS challenge, exhibited increased peripheral and brain oxidative stress, impaired neurogenesis, disrupted neurotransmitter balance, and altered glycolysis and Krebs cycle substrates. These changes also caused microglial morphological alterations, elevated C1q levels, and synaptic loss, which were associated with anxiety- and depressive-like behaviors, indicating that 4-week HFD consumption has a similar immune priming ability to a single dose of LPS injection. Extending HFD priming to 8 weeks exacerbated microglial and brain inflammation, synaptic loss, and behavioral deficits. Furthermore, prolonging the interval between priming and LPS challenge worsened inflammation and cognitive decline, suggesting the persistent effects of microglial priming.
HFD consumption persistently and time-dependently primes microglia similar to a single LPS injection, influencing immune responses and contributing to behavioral abnormalities.
This study investigates the activation and regulation of phasic store-operated calcium entry (pSOCE) in fast- and slow-twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detection in slow-twitch fibers by optimizing ionic conditions and to compare the physiological relevance of pSOCE between fiber types.
We employed mechanically skinned fast-twitch extensor digitorum longus (EDL) muscle fibers loaded with spectrally distinct Ca2+-sensitive dyes to simultaneously measure action potential-induced sarcoplasmic reticulum Ca2+ release and t-tubular system Ca2+ dynamics with millisecond resolution. Experimental conditions were optimized by reducing cytosolic Mg2+ and EGTA buffering to enhance Ca2+ release in slow-twitch soleus fibers. Confocal microscopy was used to track t-tubular system Ca2+ depletion and reuptake during electric field stimulation.
Skinned soleus fibers exhibited ~8-fold lower Ca2+ release per action potential compared to EDL fibers, yet pSOCE amplitudes were comparable. Reducing Mg2+ and EGTA levels increased Ca2+ release and left pSOCE kinetics in EDL fibers unaltered, but enabled pSOCE measurements in soleus fibers. While pSOCE in EDL fibers followed a linear dependence on the ambient Ca2+ concentration in the t-tubular system, such a relationship was violated in soleus fibers.
These findings reveal a novel, fiber-type-specific difference in pSOCE regulation. When compared to EDL fibers, soleus fibers exhibited a higher sensitivity to SOCE activation despite releasing less Ca2+ from the sarcoplasmic reticulum upon an action potential. These differences may allow soleus fibers to sustain Ca2+ homeostasis more effectively, be more resilient against disruptions in Ca2+ handling, and entail protection against disease states.
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