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Introduction: Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure and it has been shown that antioxidants attenuate cardiac remodeling in experimental models of cardiac damage. We have recently shown that FGF21, an endocrine member of the FGF family, is produced by the heart and exerts protective effects preventing cardiac hypertrophy development. The aim of the study was to determine the effects of FGF21 on oxidative stress processes in the heart.Methods: Studies in vivo were performed in hearts from wild-type (wt) and Fgf21-null mice. To assess the effects of the inflammatory process, mice were subjected to intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for 4 hr. To induce cardiac hypertrophy mice were subjected to isoproterenol (ISO) infusion for 7 days. Cell culture of neonatal cardiomyocytes from rats and mice were used for the in vitro studies. Cardiomyocytes in culture were treated with LPS for 24 hr in the presence or absence of FGF21.Results: We found that treatment of FGF21 in cardiomyocytes in culture induces the expression of genes involved in anti-oxidative pathways such as mitochondrial uncoupling proteins (UCP2 and UCP3) and superoxide dismutase-2 (SOD2). Moreover, FGF21 reduces reactive oxygen species production in cardiac cells. In keeping with this, Fgf21-null mice presented reduced expression of anti-oxidant genes in response to stimulation with LPS-induced pro-inflammatory pathways or ISO-induced cardiac hypertrophy in the heart. Moreover, we showed that FGF21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. Using neonatal cardiomyocytes in culture from wt and Fgf21-null mice we found that the FGF21 released by cardiomyocytes acts in an autocrine manner to protect the cells against oxidative stress. Finally, the analysis of samples from infarcted human hearts confirmed the association between FGF21 induction and the control of cardiac oxidative stress pathways (i.e. SOD2 induction).Conclusions: Our data indicate that FGF21 regulates in an autocrine manner genes involved in antioxidant pathways such as UCP2, UCP3 and SOD2 thus preventing reactive oxygen species production in cardiac cells. Therefore FGF21 acts in the heart as an antioxidant factor preventing pro-oxidative pathways induced by inflammatory/hypertrophic conditions. [ABSTRACT FROM AUTHOR]

Purpose: Pregnancy is a physiological model of adaptive and reversible heart enlargement. The molecular mechanisms determining physiological, non-pathological, heart enlargement are poorly known. Here we analyzed the role of the transcription factor C/EBPβ in the development of pregnancy-induced cardiac hypertrophy.Methods: We used a model of C/EBPβ haploinsufficiency (C/EBPβ+/-) in mice to determine the role of C/EBPβ in heart adaptations to pregnancy. Wild-type (Wt) and C/EBPβ+/- pregnant mice at day 18 of gestation were sacrificed, non-pregnant mice of the two genotypes at similar age served as controls. Heart was dissected and processed for microscopy analysis, and frozen for further molecular determinations. Blood was collected and glucose and triglyceride levels were measured. Plasma was used for analysis of hormonal and cytokine profile (insulin, leptin, MCP-1, interleukin-6, resistin) employing Multiplex. qPCR was used to determine gene expression levels.Results: C/EBPβ expression was increased in heart from Wt pregnant mice. Expression of other C/EBP subtypes (α and δ) was not affected by gestation. C/EBPβ+/- mice expressed C/EBPβ proteins to levels close to one-half those in Wt. Pregnancy-induced changes in systemic metabolic and hormonal profiles were not essentially different in WTs versus C/EBPβ+/- mice. C/EBPβ+/- mice developed pregnancy-induced heart hypertrophy (heart weight to tibia length ratio) to a lower extent relative to Wt mice. The increase in cardiomyocyte size observed in pregnant Wt mice did not occur in pregnant C/EBPβ+/- mice. The expression of marker genes of pathological cardiac hypertrophy, such as ANF and actinin, were unaltered due to pregnancy or to C/EBPβ haploinsufficiency. Genes involved in glucose (GLUT1 and GLUT4 transporters), and fatty acid (medium chain acyl-CoA dehydrogenase) metabolism tended to be less expressed in hearts from C/EBPβ+/- mice. Among gene markers of inflammation whose expression was analyzed in heart, interleukin-6 (IL-6) showed a marked differential behaviour in C/EBPβ+/-pregnant mice: whereas pregnancy strongly induced cardiac IL-6 expression in Wts, this phenomenon did not occur in C/EBPβ+/- mice.Conclusions: In pregnancy, heart hypertrophies and cardiomyocyte area increases as a physiological adaptive phenomenon. Here we found that normal levels of C/EBPβ are required for this phenomenon to occur. Events such as the increase in IL-6 in the heart of pregnant mice are prevented in C/EBPβ+/- animals. Thus, C/EBPβ appears as a transcription factor required for cardiac hypertrophy response to gestation. [ABSTRACT FROM AUTHOR]

Background: To cause atherosclerosis, LDLs (low-density lipoproteins) must first pass through the endothelium and then become retained in the arterial matrix. Which of these two processes is rate-limiting and predicts the topography of plaque formation remains controversial. To investigate this issue, we performed high-resolution mapping of LDL entry and retention in murine aortic arches before and during atherosclerosis development., Methods: Maps of LDL entry and retention were created by injecting fluorescently labeled LDL followed by near-infrared scanning and whole-mount confocal microscopy after 1 hour (entry) and 18 hours (retention). By comparing arches between normal mice and mice with short-term hypercholesterolemia, we analyzed changes in LDL entry and retention during the LDL accumulation phase that precedes plaque formation. Experiments were designed to secure equal plasma clearance of labeled LDL in both conditions., Results: We found that LDL retention is the overall limiting factor for LDL accumulation but that the capacity for LDL retention varied substantially over surprisingly short distances. The inner curvature region, previously considered a homogenous atherosclerosis-prone region, consisted of dorsal and ventral zones with high capacity and a central zone with low capacity for continued LDL retention. These features predicted the temporal pattern of atherosclerosis, which first appeared in the border zones and later in the central zone. The limit to LDL retention in the central zone was intrinsic to the arterial wall, possibly caused by saturation of the binding mechanism, and was lost upon conversion to atherosclerotic lesions., Conclusions: Capacity for continued LDL retention varies over short distances and predicts where and when atherosclerosis develops in the mouse aortic arch.

FGF21 is an endocrine factor that contributes to multiple pathophysiological processes, mainly via its action as a metabolic regulator and cardioprotective agent. Recent studies have shown increased circulating FGF21 levels in hypertensive patients and in mouse models of hypertension. However, the relevance of FGF21 in hypertensive heart disease has not been addressed. Hypertension was induced by treating 4-month old WT and Fgf21 -/- mice with angiotensin II (AngII) for 1 week, resulting in a similar increase in blood pressure in both genotypes. Plasma FGF21 levels and expression in heart and liver were significantly increased in hypertensive WT mice relative to controls, an effect that was associated with increased expression levels of β-klotho specifically in the heart. Fgf21 -/- mice developed a greater degree of hypertensive heart disease than WT mice, notably characterized by extensive cardiac dysfunction and fibrosis. In vitro and in vivo studies further showed that FGF21 exerted a marked protective effect against cardiac fibrosis. Finally, left ventricle biopsies from human hypertensive heart donors, especially those developing cardiomyopathy, showed a significant increase in FGF21expression compared with normotensive controls, a finding that was associated with significantly enhanced cardiac hypertrophy and fibrosis. We conclude that during hypertension, both systemic and cardiac-produced FGF21 are induced and act on the heart, protecting it from hypertensive heart disease. Thus, FGF21 acts as key factor in the fibrogenesis associated with hypertensive heart disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Angiopoietin-like protein 8 (ANGPTL8), a protein implicated in lipid and glucose homeostasis, is present only in mammals, suggesting that it is involved in processes unique to these vertebrates such as pregnancy and homeothermy. We explored the role of ANGPTL8 in maternal-fetal crosstalk and its relationship with newborn adiposity. In a longitudinal analysis of healthy pregnant women, ANGPTL8 levels decreased progressively during pregnancy although remained higher than levels in the postpartum period. In a cross-sectional observational study of women with or without gestational diabetes mellitus (GDM), and their offspring, ANGPTL8 levels were higher in venous cord blood than those in maternal blood and were significantly lower in GDM patients than those in healthy women. Infants small for gestational age and with low-fat mass had the highest ANGPTL8 cord blood levels. Studies in vitro revealed that ANGPTL8 was secreted by brown adipocytes and its expression was increased in experimental models of white-to-brown fat conversion. In addition, ANGPTL8 induced the expression of markers of brown adipocytes. The high levels of ANGPTL8 found in fetal life together with its relationship with newborn adiposity and brown adipose tissue point to ANGPTL8 as a potential new player in the modulation of the thermogenic machinery during the fetal-neonatal transition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The heart is not traditionally considered either a target or a site of fibroblast growth factor-21 (FGF21) production. However, recent findings indicate that FGF21 can act as a cardiomyokine; that is, it is produced by cardiac cells at significant levels and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key co-receptor known to confer specific responsiveness to FGF21 action. FGF21 has been demonstrated to protect against cardiac hypertrophy, cardiac inflammation, and oxidative stress. FGF21 expression in the heart is induced in response to cardiac insults, such as experimental cardiac hypertrophy and myocardial infarction in rodents, as well as in failing human hearts. Intracellular mechanisms involving PPARα and Sirt1 mediate transcriptional regulation of the FGF21 gene in response to exogenous stimuli. In humans, circulating FGF21 levels are elevated in coronary heart disease and atherosclerosis, and are associated with a higher risk of cardiovascular events in patients with type 2 diabetes. These findings provide new insights into the role of FGF21 in the heart and may offer potential therapeutic strategies for cardiac disease.

Aims: Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure, and antioxidants have been shown to attenuate cardiac remodelling in experimental models of cardiac damage. We recently showed that fibroblast growth factor 21 (Fgf21) is produced by the heart and exerts protective effects, preventing cardiac hypertrophy development. The aim of the study was to determine the effects of Fgf21 during oxidative stress signalling in the heart., Methods and Results: Fgf21 treatment in cardiomyocytes in culture induced the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3) and superoxide dismutase-2 (Sod2) and reduced ROS production. In keeping with this, expression of antioxidant genes in response to lipopolysaccharide (LPS)-induced stimulation of pro-inflammatory pathways or isoproterenol-induced cardiac hypertrophy in the heart was reduced in Fgf21-null mice. Moreover, we found that Fgf21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. This Fgf21 released by cardiomyocytes acts in an autocrine manner to protect cells against oxidative stress. Finally, failing human hearts showed up-regulation of Fgf21, Ucp3, and Sod2, confirming the association between Fgf21 induction and the control of cardiac oxidative stress pathways., Conclusion: Our data indicate that Fgf21 regulates genes involved in antioxidant pathways in an autocrine manner, thus preventing ROS production in cardiac cells. Therefore, Fgf21 acts as an antioxidant factor in the heart, preventing induction of pro-oxidative pathways by inflammatory or hypertrophic conditions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)