Hypoxia-inducible factor (HIF) 1α is a metabolic regulator that plays an important role in immunologic responses. Previous studies have demonstrated that HIF1α participates in the M1 polarization of macrophages. To clarify the mechanism of HIF1α-induced polarization of M1 macrophage, myeloid-specific HIF1α overexpression (Lysm HIF1α lsl) mice were employed and the bone marrow-derived and peritoneal macrophages were isolated. RT-PCR results revealed that HIF1α overexpression macrophage had a hyperinflammatory state characterized by the upregulation of M1 markers. Cellular bioenergetics analysis showed lower cellular oxygen consumption rates in the Lysm HIF1α lsl mice. Metabolomics studies showed that HIF1α overexpression led to increased glycolysis and pentose phosphate pathway intermediates. Further results revealed that macrophage M1 polarization, induced by HIF1α overexpression, was via upregulating the mRNA expression of the genes related to the glycolysis metabolism. Our results indicate that HIF1α promoted macrophage glycolysis metabolism, which induced M1 polarization in mice.

Highlights d Moderate cold exposure activates adipose HIF-2a signaling d Deficiency of adipocyte HIF-2a exacerbates Western-dietinduced atherosclerosis d Adipocyte HIF-2a enhances ceramide degradation by targeting ACER2 d Pharmacological activation of adipose HIF-2a reduces atherosclerosis

Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo.

Adrenomedullin (ADM) 2/intermedin (IMD) is a short peptide that belongs to the CGRP superfamily. Although it shares receptors with CGRP, ADM and amylin, ADM2 has significant and unique functions in the cardiovascular system. In the past decade, the cardiovascular effect of ADM2 has been carefully analysed. In this review, progress in understanding the effects of ADM2 on the cardiovascular system and its protective role in cardiometabolic diseases are summarized. LINKED ARTICLESThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc Abbreviations AAC, abdominal aortic constriction; ACS, acute coronary syndrome; ADM, adrenomedullin; AMPK, AMP-activated protein kinase; AMY, amylin; CRLR, calcitonin receptor-like receptor; ER, endoplasmic reticulum; I/R, ischaemia/reperfusion; RAMP, receptor activity-modifying protein; SHR, spontaneously hypertensive rat; TAC, transverse aortic contraction; VSMC, vascular smooth muscle cell Takei et al., 2004). It is one of the members of the ADM family which are all found in fish but, in mammals, only three peptides -ADM, ADM2 and ADM5 -have been found (Takei et al., 2008). These ADM peptides are themselves a part of the CGRP superfamily. ADM2 is also called intermedin (IMD), owing to its high expression in the intermediate lobe of the pituitary. Both terms, 'ADM2' and 'IMD', are widely used in the literature. However, because IMD was used as the former name for α-melanocyte stimulating hormone, we will use the terms ADM2, ADM2/IMD 1-53 , ADM2/IMD 1-47 and ADM2/IMD 1-40 in this review to avoid confusion. ADM2 shares receptors with CGRP, ADM and amylin (AMY) (Hay et al., 2005) and is widely expressed throughout the body. Recently, progress has been made on the physiological roles of ADM2 in cardiovascular homeostasis and as a protective agent against cardiometabolic diseases. In this review, the structure and expression of ADM2 and the pharmacology of ADM2, in the context of the cardiovascular system and cardiometabolic diseases, are summarized. ADM2 and ADM2 receptorsThe structure of ADM2The Adm2 gene is located on the distal arm of human chromosome 22q13.33 and encodes a pre-pro-peptide containing 148 amino acid residues with a signal sequence at the N terminus . ADM2 belongs to the CGRP superfamily, which includes α-CGRP, β-CGRP, calcitonin receptor-stimulating peptide, AMY, ADM and ADM5 (Hong et al., 2012). ADM2 shares the same structural characteristics with the other family members, including an intramolecular ring of six amino acids residues flanked by a disulfide bond and a putative amidation signal at the C terminus .Sequence alignment has shown that ADM2 shares only 28% sequence identity with its closest paralogue, ADM.However, ADM2 is highly conserved in the orthologues of different species. The mature human ADM2 shares over 60% similarity with fish and 87% identity with the rodent peptides . The property of high con...

Particulate matter with an aerodynamic diameter less than 2.5 μM (PM2.5) is one of the major environmental pollutants in China. In this study, we carried out a metabolomics profile study on PM2.5-induced inflammation. PM2.5 from Beijing, China, was collected and given to rats through intra-tracheal instillation in vivo. Acute pulmonary injury were observed by pulmonary function assessment and H.E. staining. The lipid metabolic profile was also altered with increased phospholipid and sphingolipid metabolites in broncho-alveolar lavage fluid (BALF) after PM2.5 instillation. Organic component analysis revealed that benzo[a]pyrene (BaP) is one of the most abundant and toxic components in the PM2.5 collected on the fiber filter. In vitro, BaP was used to treat A549 cells, an alveolar type II cell line. BaP (4 μM, 24 h) induced inflammation in the cells. Metabolomics analysis revealed that BaP (4 μM, 6 h) treatment altered the cellular lipid metabolic profile with increased phospholipid metabolites and reduced sphingolipid metabolites and free fatty acids (FFAs). The proportion of ω–3 polyunsaturated fatty acid (PUFA) was also decreased. Mechanically, BaP (4 μM) increased the phospholipase A2 (PLA2) activity at 4 h as well as the mRNA level of Pla2g2a at 12 h. The pro-inflammatory effect of BaP was reversed by the cytosolic PLA2 (cPLA2) inhibitor and chelator of intracellular Ca2+. This study revealed that BaP, as a component of PM2.5, induces pulmonary injury by activating PLA2 and elevating lysophosphatidylcholine (LPC) in a Ca2+-dependent manner in the alveolar type II cells.