Selenium (Se) is an essential trace element that is necessary for various metabolic processes, including protection against oxidative stress, and proper cardiovascular function. The role of Se in cardiovascular health is generally agreed upon to be essential yet not much has been defined in terms of specific functions. Se deficiency was first associated with Keshan’s Disease, an endemic disease characterized by cardiomyopathy and heart failure. Since then, Se deficiency has been associated with multiple cardiovascular diseases, including myocardial infarction, heart failure, coronary heart disease, and atherosclerosis. Se, through its incorporation into selenoproteins, is vital to maintain optimal cardiovascular health, as selenoproteins are involved in numerous crucial processes, including oxidative stress, redox regulation, thyroid hormone metabolism, and calcium flux, and inadequate Se may disrupt these processes. The present review aims to highlight the importance of Se in cardiovascular health, provide updated information on specific selenoproteins that are prominent for proper cardiovascular function, including how these proteins interact with microRNAs, and discuss the possibility of Se as a potential complemental therapy for prevention or treatment of cardiovascular disease.

A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

TLR7 (Toll-like receptor 7), the sensor for single-stranded RNA, contributes to systemic inflammation and mortality in murine polymicrobial sepsis. Recent studies show that extracellular miR-146a-5p serves as a TLR7 ligand and plays an important role in regulating host innate immunity. However, the role of miR-146a-5p and TLR7 signaling in pulmonary inflammation, endothelial activation, and sepsis-associated acute respiratory distress syndrome remains unclear. Here, we show that intratracheal administration of exogenous miR-146a-5p in mice evokes lung inflammation, activates endothelium, and increases endothelial permeability via TLR7-dependent mechanisms. TLR7 deficiency attenuates pulmonary barrier dysfunction and reduces lung inflammatory response in a murine sepsis model. Moreover, the impact of miR-146a-5p−TLR7 signaling on endothelial activation appears to be a secondary effect because TLR7 is undetectable in the human pulmonary artery and microvascular endothelial cells (ECs), which show no response to direct miR-146a-5p treatment in vitro. Both conditioned media of miR-146a-5p−treated macrophages (Mϕ) and septic sera of wild-type mice induce a marked EC barrier disruption in vitro, whereas Mϕ conditioned media or septic sera of TLR7−/− mice do not exhibit such effect. Cytokine array and pathway enrichment analysis of the Mϕ conditioned media and septic sera identify TNFα (tumor necrosis factor α) as the main downstream effector of miR-146a-5p−TLR7 signaling responsible for the EC barrier dysfunction, which is further supported by neutralizing anti-TNFα antibody intervention. Together, these data demonstrate that TLR7 activation elicits pulmonary inflammation and endothelial barrier disruption by sensing extracellular miR-146a-5p and contributes to sepsis-associated acute respiratory distress syndrome.

Deficiencies in lipid metabolism can have severe consequences for cardiac function. We previously showed that regulating glucose flux by pyruvate kinase 2 (PKM2) affects lipid synthesis and droplet abundance in cardiomyocytes. This study aims to examine how PKM2 regulates lipid metabolism in the heart. Indirect calorimetry suggested similar whole-body metabolism of PKM2 knockout (PKM2^-/-) and control (PKM2^fl/fl) young mice (2-3 months), but indicated that lipids were utilized to a greater degree in aged (1-year) PKM2^-/- mice compared to controls. Metabolic chamber studies also revealed an overall negative energy balance that contributed to reduced exercise tolerance in aged PKM2^-/- mice. Metabolomics showed substantially lower carnitine levels in PKM2^-/- cardiomyocyte fractions (CM), alongside increased circulating and cardiac dicarboxylic acids, as well as reduced mitochondrial palmitate oxidation in PKM2^-/- CM. We also noted a sex-specific difference in which female PKM2^-/- mice exhibited greater high-fat diet (HFD)-induced hyperglycemia and weight gain compared to PKM2^fl/fl females, while male PKM2^-/- mice fed a HFD were comparatively leaner than their PKM2^fl/fl counterparts. PKM2^-/- mice have aberrations in lipid metabolism that worsen with age, shifting whole-body metabolism towards a preference for lipid utilization. This may lead to a decline in aerobic capacity during exercise in aged PKM2^-/- mice. PKM2^-/- CM also display compromised mitochondrial lipid metabolism due to carnitine deficiency. Challenging PKM2^-/- mice with a HFD revealed sex-dependent differences in glycemic control and body weight. Our results indicate a role for PKM2 in sustaining the homeostasis of cardiac and whole-body lipid metabolism that contributes to overall physiological fitness.