Background:Obesity plays crucial roles in the development of cardiovascular diseases. However, the mechanisms that link obesity and cardiovascular diseases remain elusive. Compelling evidence indicates that adipokines play an important role in obesity-related cardiovascular diseases. Here, we found a new adipokine-named family with sequence similarity 19, member A5 (FAM19A5), a protein with unknown function that was predicted to be distantly related to the CC-chemokine family. We aimed to test whether adipose-derived FAM19A5 regulates vascular pathology on injury.Methods:DNA cloning, protein expression, purification, and N-terminal sequencing were applied to characterize FAM19A5. Adenovirus infection and siRNA transfection were performed to regulate FAM19A5 expression. Balloon and wire injury were performed in vivo on the rat carotid arteries and mouse femoral arteries, respectively. Bioinformatics analysis, radioactive ligand-receptor binding assays, receptor internalization, and calcium mobilization assays were used to identify the functional receptor for FAM19A5.Results:We first characterized FAM19A5 as a secreted protein, and the first 43 N-terminal amino acids were the signal peptides. Both FAM19A5 mRNA and protein were abundantly expressed in the adipose tissue but were downregulated in obese mice. Overexpression of FAM19A5 markedly inhibited vascular smooth muscle cell proliferation and migration and neointima formation in the carotid arteries of balloon-injured rats. Accordingly, FAM19A5 silencing in adipocytes significantly promoted vascular smooth muscle cell activation. Adipose-specific FAM19A5 transgenic mice showed greater attenuation of neointima formation compared with wild-type littermates fed with or without Western-style diet. We further revealed that sphingosine-1-phosphate receptor 2 was the functional receptor for FAM19A5, with a dissociation constant (Kd) of 0.634 nmol/L. Inhibition of sphingosine-1-phosphate receptor 2 or its downstream G12/13-RhoA signaling circumvented the suppressive effects of FAM19A5 on vascular smooth muscle cell proliferation and migration.Conclusions:We revealed that a novel adipokine, FAM19A5, was capable of inhibiting postinjury neointima formation via sphingosine-1-phosphate receptor 2-G12/13-RhoA signaling. Downregulation of FAM19A5 during obesity may trigger cardiometabolic diseases.

Background:The perivascular adipose tissue (PVAT) surrounding vessels constitutes a distinct functional integral layer of the vasculature required to preserve vascular tone under physiological conditions. However, there is little information on the relationship between PVAT and blood pressure regulation, including its potential contributions to circadian blood pressure variation.Methods:Using unique brown adipocyte–specific aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and angiotensinogen knockout mice, we determined the vasoactivity of homogenized PVAT in aortic rings and how brown adipocyte peripheral expression of Bmal1 and angiotensinogen in PVAT regulates the amplitude of diurnal change in blood pressure in mice.Results:We uncovered a peripheral clock in PVAT and demonstrated that loss of Bmal1 in PVAT reduces blood pressure in mice during the resting phase, leading to a superdipper phenotype. PVAT extracts from wild-type mice significantly induced contractility of isolated aortic rings in vitro in an endothelium-independent manner. This property was impaired in PVAT from brown adipocyte–selective Bmal1-deficient (BA-Bmal1-KO) mice. The PVAT contractile properties were mediated by local angiotensin II, operating through angiotensin II type 1 receptor–dependent signaling in the isolated vessels and linked to PVAT circadian regulation of angiotensinogen. Indeed, angiotensinogen mRNA and angiotensin II levels in PVAT of BA-Bmal1-KO mice were significantly reduced. Systemic infusion of angiotensin II, in turn, reduced Bmal1 expression in PVAT while eliminating the hypotensive phenotype during the resting phase in BA-Bmal1-KO mice. Angiotensinogen, highly expressed in PVAT, shows circadian expression in PVAT, and selective deletion of angiotensinogen in brown adipocytes recapitulates the phenotype of selective deletion of Bmal1 in brown adipocytes. Furthermore, angiotensinogen is a transcriptional target of Bmal1 in PVAT.Conclusions:These data indicate that local Bmal1 in PVAT regulates angiotensinogen expression and the ensuing increase in angiotensin II, which acts on smooth muscle cells in the vessel walls to regulate vasoactivity and blood pressure in a circadian fashion during the resting phase. These findings will contribute to a better understanding of the cardiovascular complications of circadian disorders, alterations in the circadian dipping phenotype, and cross-talk between systemic and peripheral regulation of blood pressure.

Anemia and iron deficiency are important and common comorbidities that often coexist in patients with heart failure. Both conditions, together or independently, are associated with poor clinical status and worse outcomes. Whether anemia and iron deficiency are just markers of heart failure severity or whether they mediate heart failure progression and outcomes and therefore should be treated is not entirely clear. Treatment of anemia in patients with heart failure with erythropoiesis-stimulating agents has been evaluated intensively during the past several years. Unfortunately, these agents did not improve outcomes but were associated with a higher risk of adverse events. Iron deficiency in patients with heart failure can be absolute, when total body iron is decreased, or functional, when total body iron is normal or increased but is inadequate to meet the needs of target tissues because of sequestration in the storage pool. Whereas iron replacement is appropriate in patients with anemia resulting from absolute iron deficiency, it has been unclear whether and how absolute or functional iron deficiency should be treated in nonanemic patients with heart failure. Recently, small studies found that administration of intravenous iron in patients with heart failure and absolute or functional iron deficiency with or without anemia improves symptoms and exercise capacity, but long-term outcomes and safety data are not yet available. In this review, we discuss the causes and pathogenesis of and treatment options for anemia and iron deficiency in patients with heart failure.

Viktor Orban's re-election to a third consecutive term in Hungary offers a preview for western countries of what the health consequences could be for governments that value populism and economic strength over the health of their people. The controversial populist was swept back into power by a wave of support, with a manifesto that included a crackdown on liberal non-governmental organisations. Orban said before the election that his opponents will face “moral, political, and legal revenge”, in the aftermath.

This week, The Lancet, publishes a Special Report on allegations of sexual harassment and abuse at UNAIDS. The report suggests that UNAIDS has at best marginalised and at worst buried allegations of sexual harassment. Its responses have been unduly weak and unacceptable, and the announcements of remediation are too little too late. Furthermore, internal loyalty to the existing leadership seems to trump integrity in the organisation, and has contributed to a culture devoid of transparency and accountability.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality in the world today. More than a million British people lived with diagnosed COPD in the UK in 2014–15, or just under 2% of the population. COPD admissions to emergency services in the UK are on the rise, but, access to treatments shown to reduce patients' time spent in hospital is still woefully inadequate.