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22 pages, 3969 KiB

Open AccessArticle

Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

by Dany Gaillard, David Masson, Erwan Garo, Maamar Souidi, Jean-Paul Pais de Barros, Kristina Schoonjans, Jacques Grober, Philippe Besnard and Charles Thomas

Int. J. Mol. Sci. 2021, 22(13), 7163; https://doi.org/10.3390/ijms22137163 - 2 Jul 2021

Cited by 7 | Viewed by 3481

Abstract

Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of [...] Read more.

Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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16 pages, 3344 KiB

Open AccessArticle

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes

by Lejla Medzikovic, Hylja Heese, Pieter B. van Loenen, Cindy P. A. A. van Roomen, Ingeborg B. Hooijkaas, Vincent M. Christoffels, Esther E. Creemers, Carlie J. M. de Vries and Vivian de Waard

Int. J. Mol. Sci. 2021, 22(4), 1600; https://doi.org/10.3390/ijms22041600 - 5 Feb 2021

Cited by 14 | Viewed by 3111

Abstract

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts [...] Read more.

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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Review

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25 pages, 1120 KiB

Open AccessReview

Nuclear Receptors and Clock Components in Cardiovascular Diseases

by Benoit Pourcet and Hélène Duez

Int. J. Mol. Sci. 2021, 22(18), 9721; https://doi.org/10.3390/ijms22189721 - 8 Sep 2021

Cited by 6 | Viewed by 3957

Abstract

Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and [...] Read more.

Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and smoking, the alteration of circadian rhythms, in shift workers for instance, has recently been recognized as an additional risk factor. Accordingly, targeting a pro-atherogenic pathway at the right time window, namely chronotherapy, has proven its efficiency in reducing plaque progression without affecting healthy tissues in mice, thus providing the rationale of such an approach to treat CVD and to reduce drug side effects. Nuclear receptors are transcriptional factors involved in the control of many physiological processes. Among them, Rev-erbs and RORs control metabolic homeostasis, inflammatory processes and the biological clock. In this review, we discuss the opportunity to dampen atherosclerosis progression by targeting such ligand-activated core clock components in a (chrono-)therapeutic approach in order to treat CVD. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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35 pages, 2806 KiB

Open AccessReview

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

by Ana Paredes, Rocio Santos-Clemente and Mercedes Ricote

Int. J. Mol. Sci. 2021, 22(15), 7775; https://doi.org/10.3390/ijms22157775 - 21 Jul 2021

Cited by 9 | Viewed by 4735

Abstract

The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests [...] Read more.

The heart is the first organ to acquire its physiological function during development, enabling it to supply the organism with oxygen and nutrients. Given this early commitment, cardiomyocytes were traditionally considered transcriptionally stable cells fully committed to contractile function. However, growing evidence suggests that the maintenance of cardiac function in health and disease depends on transcriptional and epigenetic regulation. Several studies have revealed that the complex transcriptional alterations underlying cardiovascular disease (CVD) manifestations such as myocardial infarction and hypertrophy is mediated by cardiac retinoid X receptors (RXR) and their partners. RXRs are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and drive essential biological processes such as ion handling, mitochondrial biogenesis, and glucose and lipid metabolism. RXRs are thus attractive molecular targets for the development of effective pharmacological strategies for CVD treatment and prevention. In this review, we summarize current knowledge of RXR partnership biology in cardiac homeostasis and disease, providing an up-to-date view of the molecular mechanisms and cellular pathways that sustain cardiomyocyte physiology. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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21 pages, 924 KiB

Open AccessReview

Roles of Nuclear Receptors in Vascular Calcification

by Giulia Chinetti and Jaap G. Neels

Int. J. Mol. Sci. 2021, 22(12), 6491; https://doi.org/10.3390/ijms22126491 - 17 Jun 2021

Cited by 4 | Viewed by 3732

Abstract

Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated [...] Read more.

Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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14 pages, 1022 KiB

Open AccessReview

Estrogen Receptor Functions and Pathways at the Vascular Immune Interface

by Aida Dama, Chiara Baggio, Carlotta Boscaro, Mattia Albiero and Andrea Cignarella

Int. J. Mol. Sci. 2021, 22(8), 4254; https://doi.org/10.3390/ijms22084254 - 20 Apr 2021

Cited by 24 | Viewed by 5897

Abstract

Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of [...] Read more.

Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes. Gender dependence of endothelial biology, either through the action of sex hormones or sex chromosome-related factors, is becoming increasingly evident. Accordingly, cardiometabolic risk increases as women transition to menopause. Estrogen pathways control angiogenesis progression through complex mechanisms. The classic ERs have been acknowledged to function in mediating estrogen effects on glucose metabolism, but 17β-estradiol also rapidly promotes endothelial glycolysis by increasing glucose transporter 1 (GLUT1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels through GPER-dependent mechanisms. Estrogens alter monocyte and macrophage phenotype(s), and induce effects on other estrogen-responsive cell lineages (e.g., secretion of cytokines/chemokines/growth factors) that impact macrophage function. The pharmacological modulation of ERs for therapeutic purposes, however, is particularly challenging due to the lack of ER subtype selectivity of currently used agents. Identifying the determinants of biological responses to estrogenic agents at the vascular immune interface and developing targeted pharmacological interventions may result in novel improved therapeutic solutions. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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18 pages, 1437 KiB

Open AccessReview

Vitamin D and Cardiovascular Disease: An Updated Narrative Review

by Armin Zittermann, Christian Trummer, Verena Theiler-Schwetz, Elisabeth Lerchbaum, Winfried März and Stefan Pilz

Int. J. Mol. Sci. 2021, 22(6), 2896; https://doi.org/10.3390/ijms22062896 - 12 Mar 2021

Cited by 68 | Viewed by 8412

Abstract

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin [...] Read more.

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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14 pages, 260 KiB

Open AccessReview

PPARs and Myocardial Infarction

by Kay-Dietrich Wagner and Nicole Wagner

Int. J. Mol. Sci. 2020, 21(24), 9436; https://doi.org/10.3390/ijms21249436 - 11 Dec 2020

Cited by 23 | Viewed by 3459

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. They exhibit tissue and cell type-specific expression patterns and functions. Besides the established notion of the therapeutic potential of PPAR agonists for the treatment of glucose and lipid disorders, more recent data propose specific PPAR ligands as potential therapies for cardiovascular diseases. In this review, we focus on the knowledge of PPAR function in myocardial infarction, a severe pathological condition for which therapeutic use of PPAR modulation has been suggested. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cardiovascular Disease)

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