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1.
Cardiovasc Drugs Ther ; 35(5): 939-951, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-32671602

RESUMEN

PURPOSE: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in the developed world and is currently undertreated due to the complicated nature of the disease. Herein, we aimed to address the therapeutic potential of a novel class of pleiotropic mediators, specifically a new drug candidate, nitro-oleic acid (NO2-OA), on AAA, in a well-characterized murine AAA model. METHODS: We generated AAA using a mouse model combining AAV.PCSK9-D377Y induced hypercholesterolemia with angiotensin II given by chronic infusion. Vehicle control (PEG-400), oleic acid (OA), or NO2-OA were subcutaneously delivered to mice using an osmotic minipump. We characterized the effects of NO2-OA on pathophysiological responses and dissected the underlying molecular mechanisms through various in vitro and ex vivo strategies. RESULTS: Subcutaneous administration of NO2-OA significantly decreased the AAA incidence (8/28 mice) and supra-renal aorta diameters compared to mice infused with either PEG-400 (13/19, p = 0.0117) or OA (16/23, p = 0.0078). In parallel, the infusion of NO2-OA in the AAA model drastically decreased extracellular matrix degradation, inflammatory cytokine levels, and leucocyte/macrophage infiltration in the vasculature. Administration of NO2-OA reduced inflammation, cytokine secretion, and cell migration triggered by various biological stimuli in primary and macrophage cell lines partially through activation of the peroxisome proliferator-activated receptor-gamma (PPARγ). Moreover, the protective effect of NO2-OA relies on the inhibition of macrophage prostaglandin E2 (PGE2)-induced PGE2 receptor 4 (EP4) cAMP signaling, known to participate in the development of AAA. CONCLUSION: Administration of NO2-OA protects against AAA formation and multifactorial macrophage activation. With NO2-OA currently undergoing FDA approved phase II clinical trials, these findings may expedite the use of this nitro-fatty acid for AAA therapy.


Asunto(s)
Aneurisma de la Aorta Abdominal/fisiopatología , Activación de Macrófagos/efectos de los fármacos , Nitrocompuestos/farmacología , Ácidos Oléicos/farmacología , Angiotensina II/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos
2.
Physiol Genomics ; 51(6): 224-233, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31074702

RESUMEN

Endothelial cell (EC) dysfunction is a crucial initiation event in the development of atherosclerosis and is associated with diabetes mellitus, hypertension, and heart failure. Both digestive and oxidative inflammatory conditions lead to the endogenous formation of nitrated derivatives of unsaturated fatty acids (FAs) upon generation of the proximal nitrating species nitrogen dioxide (·NO2) by nitric oxide (·NO) and nitrite-dependent reactions. Nitro-FAs (NO2-FAs) such as nitro-oleic acid (NO2-OA) and nitro-linoleic acid (NO2-LA) potently inhibit inflammation and oxidative stress, regulate cellular functions, and maintain cardiovascular homeostasis. Recently, conjugated linoleic acid (CLA) was identified as the preferential FA substrate of nitration in vivo. However, the functions of nitro-CLA (NO2-CLA) in ECs remain to be explored. In the present study, a distinct transcriptome regulated by NO2-CLA was revealed in primary human coronary artery endothelial cells (HCAECs) through RNA sequencing. Differential gene expression and pathway enrichment analysis identified numerous regulatory networks including those related to the modulation of inflammation, oxidative stress, cell cycle, and hypoxic responses by NO2-CLA, suggesting a diverse impact of NO2-CLA and other electrophilic nitrated FAs on cellular processes. These findings extend the understanding of the protective actions of NO2-CLA in cardiovascular diseases and provide new insight into the underlying mechanisms that mediate the pleiotropic cellular responses to NO2-CLA.


Asunto(s)
Células Endoteliales/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Ácidos Linoleicos Conjugados/farmacología , Adulto , Sistema Cardiovascular/efectos de los fármacos , Células Cultivadas , Redes Reguladoras de Genes/genética , Homeostasis/efectos de los fármacos , Homeostasis/genética , Humanos , Inflamación/genética , Masculino , Óxido Nítrico/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Transcriptoma/efectos de los fármacos , Transcriptoma/genética
3.
Arterioscler Thromb Vasc Biol ; 38(8): 1738-1747, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29954752

RESUMEN

Objective- Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPARγ (peroxisome proliferator-activated receptor γ) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPARγ-KO (brown adipocyte-specific PPARγ knockout) mice. Approach and Results- Deletion of PPARγ in brown adipocytes did not affect PPARγ in white adipocytes or vascular smooth muscle cells or PPARα and PPARδ expression in brown adipocytes. However, development of PVAT and interscapular brown adipose tissue was remarkably impaired, associated with reduced expression of genes encoding lipogenic enzymes in the BA-PPARγ-KO mice. Thermogenesis in brown adipose tissue was significantly impaired with reduced expression of thermogenesis genes in brown adipose tissue and compensatory increase in subcutaneous and gonadal white adipose tissues. Remarkably, basal expression of inflammatory genes and macrophage infiltration in PVAT and brown adipose tissue were significantly increased in the BA-PPARγ-KO mice. BA-PPARγ-KO mice were crossbred with ApoE KO (apolipoprotein E knockout) mice to investigate the development of atherosclerosis. Flow cytometry analysis confirmed increased systemic and PVAT inflammation. Consequently, atherosclerotic lesions were significantly increased in mice with impaired PVAT development, thus indicating that the lack of normal PVAT is sufficient to drive increased atherosclerosis. Conclusions- PPARγ is required for functional PVAT development. PPARγ deficiency in PVAT, while still expressed in vascular smooth muscle cell, enhances atherosclerosis and results in vascular and systemic inflammation, providing new insights on the specific roles of PVAT in atherosclerosis and cardiovascular disease at large.


Asunto(s)
Adipocitos Marrones/metabolismo , Adipogénesis , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , PPAR gamma/deficiencia , Adipocitos Marrones/patología , Tejido Adiposo Pardo/patología , Tejido Adiposo Pardo/fisiopatología , Tejido Adiposo Blanco/patología , Tejido Adiposo Blanco/fisiopatología , Adiposidad , Animales , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/fisiopatología , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Mediadores de Inflamación/metabolismo , Lipogénesis/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , PPAR gamma/genética , Placa Aterosclerótica , Transducción de Señal , Termogénesis
4.
Physiol Genomics ; 50(4): 287-295, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29473818

RESUMEN

Nitro-conjugated linoleic acid (NO2-CLA) is formed by metabolic and inflammatory reactions of nitric oxide and nitrite, and represents the most abundant nitro-fatty acid species in humans. These electrophilic fatty acid nitroalkene derivatives mediate pleiotropic cell signaling responses. Here, we report a systematic approach to investigate the effect of NO2-CLA on human coronary artery smooth muscle cells (hCASMC), based on the RNA-Seq and bioinformatics analysis. There were extensive differentially expressed genes in NO2-CLA vs. control (510) and NO2-CLA vs. CLA (272) treatment groups, respectively. Notably, only minimal alterations were observed in CLA vs. control conditions, indicating that the electrophilic character of NO2-CLA is requited to induce differential gene expression responses independently from native CLA. Functional enrichment analysis of differentially expressed genes reveals multiple cellular processes to be affected under NO2-CLA treatment, including cell proliferation, lipid metabolism, antioxidant and inflammatory-related gene expression responses. These findings reveal that nitro-fatty acid derivatives such as NO2-CLA regulate a broad array of adaptive gene expression responses by hCASMC.


Asunto(s)
Ácidos Linoleicos Conjugados/farmacología , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Biología Computacional/métodos , Vasos Coronarios/citología , Vasos Coronarios/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Humanos , Metabolismo de los Lípidos/genética , Transducción de Señal/efectos de los fármacos
5.
Nitric Oxide ; 2018 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-29578057

RESUMEN

The addition of nitrogen dioxide (NO2) to the double bond of unsaturated fatty acids yields an array of electrophilic nitro-fatty acids (NO2-FA) with unique biochemical and signaling properties. During the last decade, NO2-FA have been shown to exert a protective role in various inflammatory and metabolic disorders. NO2-FA exert their biological effects primarily by regulating two central physiological adaptive responses: the canonical inflammatory signaling and metabolic pathways. In this mini-review, we summarize current knowledge on the regulatory role of NO2-FA in the inflammatory and metabolic response via regulation of nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ), master regulators of inflammation and metabolism. Moreover, the engagement of novel signaling and metabolic pathways influenced by NO2-FA, beyond NF-κB and PPAR signaling, is discussed herein.

7.
Redox Biol ; 74: 103202, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38865901

RESUMEN

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a ß-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.


Asunto(s)
Alquenos , Inflamación , Proteínas de la Membrana , Nitrocompuestos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Animales , Inflamación/tratamiento farmacológico , Humanos , Ratones , Alquenos/química , Alquenos/farmacología , Nitrocompuestos/química , Nitrocompuestos/farmacología , Relación Estructura-Actividad
8.
J Biol Chem ; 287(50): 41651-66, 2012 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-23060450

RESUMEN

12/15-Lipoxygenases (LOXs) in monocytes and macrophages generate novel phospholipid-esterified eicosanoids. Here, we report the generation of two additional families of related lipids comprising 15-ketoeicosatetraenoic acid (KETE) attached to four phosphatidylethanolamines (PEs). The lipids are generated basally by 15-LOX in IL-4-stimulated monocytes, are elevated on calcium mobilization, and are detected at increased levels in bronchoalveolar lavage fluid from cystic fibrosis patients (3.6 ng/ml of lavage). Murine peritoneal macrophages generate 12-KETE-PEs, which are absent in 12/15-LOX-deficient mice. Inhibition of 15-prostaglandin dehydrogenase prevents their formation from exogenous 15-hydroxyeicosatetraenoic acid-PE in human monocytes. Both human and murine cells also generated analogous hydroperoxyeicosatetraenoic acid-PEs. The electrophilic reactivity of KETE-PEs is shown by their Michael addition to glutathione and cysteine. Lastly, both 15-hydroxyeicosatetraenoic acid-PE and 15-KETE-PE activated peroxisome proliferator-activated receptor-γ reporter activity in macrophages in a dose-dependent manner. In summary, we demonstrate novel peroxisome proliferator-activated receptor-γ-activating oxidized phospholipids generated enzymatically by LOX and 15-prostaglandin dehydrogenase in primary monocytic cells and in a human Th2-related lung disease. The lipids are a new family of bioactive mediators from the 12/15-LOX pathway that may contribute to its known anti-inflammatory actions in vivo.


Asunto(s)
Fibrosis Quística/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Peritoneales/metabolismo , Monocitos/metabolismo , PPAR gamma/metabolismo , Fosfatidiletanolaminas/metabolismo , Animales , Araquidonato 12-Lipooxigenasa/metabolismo , Araquidonato 15-Lipooxigenasa/metabolismo , Ácidos Araquidónicos/metabolismo , Fibrosis Quística/patología , Femenino , Humanos , Macrófagos Alveolares/patología , Macrófagos Peritoneales/patología , Masculino , Ratones , Monocitos/patología
9.
Circulation ; 126(9): 1067-78, 2012 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-22855570

RESUMEN

BACKGROUND: Perivascular adipose tissue (PVAT) surrounds most vessels and shares common features with brown adipose tissue (BAT). Although adaptive thermogenesis in BAT increases energy expenditure and is beneficial for metabolic diseases, little is known about the role of PVAT in vascular diseases such as atherosclerosis. We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis. METHODS AND RESULTS: PVAT shares similar structural and proteomics with BAT. We demonstrated that PVAT has thermogenic properties similar to BAT in response to cold stimuli in vivo. Proteomics analysis of the PVAT from mice housed in a cold environment identified differential expression in proteins highly related to cellular metabolic processes. In a mouse model deficient in peroxisome proliferator-activated receptor-γ in smooth muscle cells (SMPG KO mice), we uncovered a complete absence of PVAT surrounding the vasculature, likely caused by peroxisome proliferator-activated receptor-γ deletion in the perivascular adipocyte precursor cells as well. Lack of PVAT, which results in loss of its thermogenic activity, impaired vascular homeostasis, which caused temperature loss and endothelial dysfunction. We further showed that cold exposure inhibits atherosclerosis and improves endothelial function in mice with intact PVAT but not in SMPG KO mice as a result of impaired lipid clearance. Proinflammatory cytokine expression in PVAT is not altered on exposure to cold. Finally, prostacyclin released from PVAT contributes to the vascular protection against endothelial dysfunction. CONCLUSIONS: PVAT is a vasoactive organ with functional characteristics similar to BAT and is essential for intravascular thermoregulation of cold acclimation. This thermogenic capacity of PVAT plays an important protective role in the pathogenesis of atherosclerosis.


Asunto(s)
Tejido Adiposo/fisiopatología , Aterosclerosis/etiología , Regulación de la Temperatura Corporal/fisiología , Músculo Liso Vascular/fisiopatología , PPAR gamma/deficiencia , Adaptación Fisiológica/fisiología , Adipocitos/metabolismo , Tejido Adiposo/patología , Tejido Adiposo Pardo/metabolismo , Animales , Aorta , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/prevención & control , Arterias Carótidas , Frío , Citocinas/metabolismo , Dieta Aterogénica , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Regulación de la Expresión Génica/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/patología , PPAR gamma/genética , Prostaglandinas I/fisiología , Proteómica
10.
Circ Res ; 107(4): 540-8, 2010 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-20558825

RESUMEN

RATIONALE: Nitro-oleic acid (OA-NO(2)) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO(2) exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature. OBJECTIVE: The present study sought to investigate the protective role of OA-NO(2) in angiotensin (Ang) II-induced hypertension. METHODS AND RESULTS: We show that systemic administration of OA-NO(2) results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO(2) significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT(1)R)-mediated signaling because vascular contraction by other G-protein-coupled receptors is not altered in response to OA-NO(2) treatment. From the mechanistic viewpoint, OA-NO(2) lowers Ang II-induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)gamma activation. Rather, OA-NO(2), but not OA, specifically binds to the AT(1)R, reduces heterotrimeric G-protein coupling, and inhibits IP(3) (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. CONCLUSIONS: These results demonstrate that OA-NO(2) diminishes the pressor response to Ang II and inhibits AT(1)R-dependent vasoconstriction, revealing OA-NO(2) as a novel antagonist of Ang II-induced hypertension.


Asunto(s)
Angiotensina II/antagonistas & inhibidores , Angiotensina II/toxicidad , Hipertensión/inducido químicamente , Hipertensión/prevención & control , Nitrocompuestos/uso terapéutico , Ácido Oléico/uso terapéutico , Angiotensina II/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Ácidos Linoleicos/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ácidos Oléicos/uso terapéutico , Ratas , Ratas Sprague-Dawley
11.
Circulation ; 119(16): 2161-9, 2009 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-19364979

RESUMEN

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists are commonly used to treat diabetes, although their PPARgamma-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPARgamma experimental models suggest an important pleiotropic role for PPARgamma in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell-specific PPARgamma in basal vascular tone. METHODS AND RESULTS: We show that vascular smooth muscle cell-selective deletion of PPARgamma impairs vasoactivity with an overall reduction in BP. Aortic contraction in response to norepinephrine is reduced and vasorelaxation is enhanced in response to beta-adrenergic receptor (beta-AdR) agonists in vitro. Similarly, vascular smooth muscle cell-selective PPARgamma knockout mice display a biphasic response to norepinephrine in BP, reversible on administration of beta-AdR blocker, and enhanced BP reduction on treatment with beta-AdR agonists. Consistent with enhanced beta2-AdR responsiveness, we found that the absence of PPARgamma in vascular smooth muscle cells increased beta2-AdR expression, possibly leading to the hypotensive phenotype during the rest phase. CONCLUSIONS: These data uncovered the beta2-AdR as a novel target of PPARgamma transcriptional repression in vascular smooth muscle cells and indicate that PPARgamma regulation of beta2-adrenergic signaling is important in the modulation of BP.


Asunto(s)
Presión Sanguínea/fisiología , Hipotensión/genética , Hipotensión/fisiopatología , Músculo Liso Vascular/fisiología , PPAR gamma/genética , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Regulación de la Expresión Génica/fisiología , Hipotensión/inducido químicamente , Ratones , Ratones Noqueados , Norepinefrina/farmacología , PPAR gamma/agonistas , PPAR gamma/metabolismo , Regiones Promotoras Genéticas/fisiología , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tiazolidinedionas/farmacología , Transcripción Genética/fisiología , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología
12.
Biochem Biophys Res Commun ; 397(2): 239-44, 2010 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-20493166

RESUMEN

Nitroalkene derivatives of nitro-linoleic acid (LNO(2)) and nitro-oleic acid (OA-NO(2)) are nitrated unsaturated fatty acids that can be detected in healthy human plasma, red blood cells and urine. It has been shown that nitroalkenes have potent anti-inflammatory properties in multiple disease models. In the present study, we are the first to investigate the apoptotic effects of nitroalkenes in rat aortic smooth muscle cells (RASMCs). We observed that nitroalkenes induce RASMCs apoptosis in a dose-dependent manner. In addition, nitroalkenes stimulate extrinsic caspase-8 and intrinsic caspase-9 activity to trigger the caspase-3 apoptotic signaling cascade, resulting in RASMCs death. Furthermore, the pro-apoptotic protein, Bad was upregulated and antiapoptotic protein, Bcl-xl was downregulated during nitroalkene-induced apoptosis. These results demonstrate that nitroalkenes can induce RASMCs apoptosis via stimulation of caspase activity and the regulation of apoptotic protein expression levels.


Asunto(s)
Alquenos/farmacología , Apoptosis , Caspasas/biosíntesis , Ácidos Linoleicos/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Nitrocompuestos/farmacología , Ácidos Oléicos/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/enzimología , Células Cultivadas , Activación Enzimática , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/enzimología , Ratas , Proteína Letal Asociada a bcl/biosíntesis , Proteína bcl-X/antagonistas & inhibidores
13.
Arterioscler Thromb Vasc Biol ; 29(11): 1843-50, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19592468

RESUMEN

BACKGROUND: Reactive oxygen species (ROS) play an important role in the maintenance of cardiovascular homeostasis. The present study sought to determine whether nuclear factor erythroid-2 related factor 2 (Nrf2), a master gene of the endogenous antioxidant defense system, is a critical regulator of the cardiac hypertrophic response to pathological stress. METHODS AND RESULTS: Cardiac hypertrophy and dysfunction were established in mice by transverse aortic constriction (TAC). Nrf2 expression was transiently increased and then declined to the basal level while impairment of cardiac function proceeded. The knockout of Nrf2 (Nrf2(-/-)) did not cause any apparent structural and functional abnormalities in the unstressed heart. However, Nrf2(-/-) mice after TAC developed pathological cardiac hypertrophy, significant myocardial fibrosis and apoptosis, overt heart failure, and increased mortality, which were associated with elevated myocardial levels of 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine and a complete blockade of the myocardial expression of several antioxidant genes. Overexpression of Nrf2 dramatically inhibited hypertrophic factor-induced ROS production and growth in both cardiomyocytes and cardiac fibroblasts, whereas knockdown of Nrf2 exerted opposite effects in both cells. CONCLUSIONS: These findings demonstrate that activation of Nrf2 provides a novel mechanism to protect the murine heart against pathological cardiac hypertrophy and heart failure via suppressing oxidative stress.


Asunto(s)
Cardiomegalia/metabolismo , Cardiomegalia/patología , Factor 2 Relacionado con NF-E2/metabolismo , Remodelación Ventricular/fisiología , Animales , Apoptosis/genética , Apoptosis/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Hemodinámica , Ratones , Ratones Noqueados , Miocitos Cardíacos/citología , Miocitos Cardíacos/patología , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo , Probabilidad , Distribución Aleatoria , Especies Reactivas de Oxígeno/metabolismo , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y Especificidad , Transducción de Señal , Regulación hacia Arriba
14.
Sci Transl Med ; 12(572)2020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-33268508

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 (AGXT1). Genetic (Agxt1 -/- mice) and dietary approaches to limit glycine availability resulted in exacerbated diet-induced hyperlipidemia and steatohepatitis, with suppressed mitochondrial/peroxisomal fatty acid ß-oxidation (FAO) and enhanced inflammation as the underlying pathways. We explored glycine-based compounds with dual lipid/glucose-lowering properties as potential therapies for NAFLD and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that improved body composition and lowered circulating glucose, lipids, transaminases, proinflammatory cytokines, and steatohepatitis in mice with established NASH induced by a high-fat, cholesterol, and fructose diet. We applied metagenomics, transcriptomics, and metabolomics to explore the underlying mechanisms. The bacterial genus Clostridium sensu stricto was markedly increased in mice with NASH and decreased after DT-109 treatment. DT-109 induced hepatic FAO pathways, lowered lipotoxicity, and stimulated de novo glutathione synthesis. In turn, inflammatory infiltration and hepatic fibrosis were attenuated via suppression of NF-κB target genes and TGFß/SMAD signaling. Unlike its effects on the gut microbiome, DT-109 stimulated FAO and glutathione synthesis independent of NASH. In conclusion, impaired glycine metabolism may play a causative role in NAFLD. Glycine-based treatment attenuates experimental NAFLD by stimulating hepatic FAO and glutathione synthesis, thus warranting clinical evaluation.


Asunto(s)
Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa , Ácidos Grasos , Glutatión , Glicina , Humanos , Hígado , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico
15.
Nat Commun ; 11(1): 6417, 2020 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-33339817

RESUMEN

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.


Asunto(s)
Enfermedades Cardiovasculares/genética , Genoma Humano , Mutación con Pérdida de Función/genética , Terapia Molecular Dirigida , Bancos de Muestras Biológicas , Enfermedades Cardiovasculares/sangre , Silenciador del Gen , Marcación de Gen , Estudio de Asociación del Genoma Completo , Humanos , Lípidos/sangre , Hígado/metabolismo , Fenómica , Receptores de LDL/genética , Reino Unido
16.
Clin Sci (Lond) ; 116(3): 205-18, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19118492

RESUMEN

The relevance of PPARgamma (peroxisome-proliferator-activated receptor gamma) as an important therapeutic target for the treatment of diabetes arises from its hypoglycaemic effects in diabetic patients and also from the critical role in the regulation of cardiovascular functions. From a clinical perspective, differences between current FDA (Food and Drug Administration)-approved PPARgamma drugs have been observed in terms of atherosclerosis and cardiac and stroke events. The adverse effects of PPARgamma-specific treatments that hamper their cardiovascular protective roles, affirm the strong need to evaluate the efficacy of the current drugs. Therefore active research is directed towards high-throughput screening and pharmacological testing of a plethora of newly identified natural or synthetic compounds. In the present review we describe the rationale behind drug design strategies targeting PPARgamma, based on current knowledge regarding the effects of such drugs in experimental animal models, as well as in clinical practice. Regarding endogenous PPARgamma ligands, several fatty acid derivatives bind PPARgamma with different affinities, although the physiological relevance of these interactions is not always evident. Recently, NO-derived unsaturated fatty acids were found to be potent agonists of PPARs, with preferential affinity for PPARgamma, compared with oxidized fatty acid derivatives. Nitroalkenes exert important bioactivities of relevance for the cardiovascular system including anti-inflammatory and antiplatelet actions, and are important mediators of vascular tone. A new generation of insulin sensitizers with PPARgamma function for the treatment of diabetes may serve to limit patients from the increased cardiovascular burden of this disease.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/fisiopatología , PPAR gamma/fisiología , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Ligandos , Ratones , PPAR gamma/agonistas , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/uso terapéutico
17.
EBioMedicine ; 41: 62-72, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30772307

RESUMEN

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. METHODS: Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. FINDINGS: CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. INTERPRETATION: OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Animales , Metabolismo Energético , Lipogénesis , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ácidos Oléicos/administración & dosificación , Ácidos Oléicos/farmacología , Proteolisis , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismo
18.
Redox Biol ; 15: 522-531, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29413964

RESUMEN

Conjugated linoleic acid (CLA) is a prime substrate for intra-gastric nitration giving rise to the formation of nitro-conjugated linoleic acid (NO2-CLA). Herein, NO2-CLA generation is demonstrated within the context of acute inflammatory responses both in vitro and in vivo. Macrophage activation resulted in dose- and time-dependent CLA nitration and also in the production of secondary electrophilic and non-electrophilic derivatives. Both exogenous NO2-CLA as well as that generated in situ, attenuated NF-κB-dependent gene expression, decreased pro-inflammatory cytokine production and up-regulated Nrf2-regulated proteins. Importantly, both CLA nitration and the corresponding downstream anti-inflammatory actions of NO2-CLA were recapitulated in a mouse peritonitis model where NO2-CLA administration decreased pro-inflammatory cytokines and inhibited leukocyte recruitment. Taken together, our results demonstrate that the formation of NO2-CLA has the potential to function as an adaptive response capable of not only modulating inflammation amplitude but also protecting neighboring tissues via the expression of Nrf2-dependent genes.


Asunto(s)
Inmunoconjugados/metabolismo , Inflamación/metabolismo , Ácidos Linoleicos Conjugados/metabolismo , Óxido Nítrico/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Inmunoconjugados/inmunología , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Ácidos Linoleicos Conjugados/inmunología , Ácidos Linoleicos Conjugados/farmacología , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/química , Óxido Nítrico/inmunología , Transducción de Señal
19.
Mol Aspects Med ; 28(5-6): 507-37, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17624419

RESUMEN

The protective effect of vitamins E (alpha-tocopherol) and C (L-ascorbic acid) in the prevention of cardiovascular disease (CVD) has been shown in a number of situations but a secure correlation is not universally accepted. Under certain conditions, both, L-ascorbic acid and alpha-tocopherol can exhibit antioxidant properties and thus may reduce the formation of oxidized small molecules, proteins and lipids, which are a possible cause of cellular de-regulation. However, non-antioxidant effects have also been suggested to play a role in the prevention of atherosclerosis. Vitamin E and C can modulate signal transduction and gene expression and thus affect many cellular reactions such as the proliferation of smooth muscle cells, the expression of cell adhesion and extracellular matrix molecules, the production of O(2)(-) by NADPH-oxidase, the aggregation of platelets and the inflammatory response. Vitamins E and C may modulate the extracellular matrix environment by affecting VSMC differentiation and the expression of connective tissue proteins involved in vascular remodeling as well as the maintenance of vascular wall integrity. This review summarizes individually the molecular activities of vitamins E and C on the cells within the connective tissue of the vasculature, which are centrally involved in the maintenance of an intact vascular wall as well as in the repair of atherosclerotic lesions during disease development.


Asunto(s)
Ácido Ascórbico/metabolismo , Vasos Sanguíneos/metabolismo , Matriz Extracelular/metabolismo , Vitamina E/metabolismo , Animales , Ácido Ascórbico/química , Enfermedades Cardiovasculares/prevención & control , Humanos , Vitamina E/química
20.
Biofactors ; 43(1): 42-53, 2017 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-27355903

RESUMEN

Curcumin, a polyphenol from turmeric (Curcuma longa), reduces inflammation, atherosclerosis, and obesity in several animal studies. In Ldlr-/- mice fed a high-fat diet (HFD), curcumin reduces plasma lipid levels, therefore contributing to a lower accumulation of lipids and to reduced expression of fatty acid transport proteins (CD36/FAT, FABP4/aP2) in peritoneal macrophages. In this study, we analyzed the molecular mechanisms by which curcumin (500, 1000, 1500 mg/kg diet, for 4 months) may influence plasma and tissue lipid levels in Ldlr-/- mice fed an HFD. In liver, HFD significantly suppressed cAMP levels, and curcumin restored almost normal levels. Similar trends were observed in adipose tissues, but not in brain, skeletal muscle, spleen, and kidney. Treatment with curcumin increased phosphorylation of CREB in liver, what may play a role in regulatory effects of curcumin in lipid homeostasis. In cell lines, curcumin increased the level of cAMP, activated the transcription factor CREB and the human CD36 promoter via a sequence containing a consensus CREB response element. Regulatory effects of HFD and Cur on gene expression were observed in liver, less in skeletal muscle and not in brain. Since the cAMP/protein kinase A (PKA)/CREB pathway plays an important role in lipid homeostasis, energy expenditure, and thermogenesis by increasing lipolysis and fatty acid ß-oxidation, an increase in cAMP levels induced by curcumin may contribute to its hypolipidemic and anti-atherosclerotic effects. © 2016 BioFactors, 43(1):42-53, 2017.


Asunto(s)
Antígenos CD36/metabolismo , Curcumina/farmacología , AMP Cíclico/metabolismo , Dieta Alta en Grasa , Hipolipemiantes/farmacología , Animales , Secuencia de Bases , Sitios de Unión , Antígenos CD36/genética , Línea Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Evaluación Preclínica de Medicamentos , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional
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