Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle

Ibarra-Lara, Luz; Valle-Mondragón, Leonardo Del; Soria-Castro, Elizabeth; Torres-Narváez, Juan Carlos; Pérez-Severiano, Francisca; Sánchez-Aguilar, María; Ramírez-Ortega, Margarita; Cervantes-Pérez, Luz Graciela; Pastelín-Hernández, Gustavo; Oidor-Chan, Víctor Hugo; Zarco-Olvera, Gabriela; Sánchez-Mendoza, Alicia

doi:10.1016/j.pharep.2016.03.002

Cited by 18 publications

(17 citation statements)

References 29 publications

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“…Beneficial effects of fenofibrate might be explained by its triglyceride-lowering effect and by PPAR-α activation [ 11 , 18 ]. PPAR-α stimulation protects the heart during ischemia by regulating myocardial metabolism, increasing antioxidant defenses, decreasing ROS and modifying RAS participation [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…TAC was determined following the method as previously reported by Ibarra-Lara et al [ 15 ] based on the reduction of Cu 2+ to Cu 1+ .…”

Section: Methodsmentioning

confidence: 99%

“…Myocardial Ang II, MDA, BH 2 and BH 4 , production was evaluated by capillary zone electrophoresis (CZE), according to the methods described previously [ 15 ]. Data are expressed as pmol of metabolite per mg of protein.…”

Section: Methodsmentioning

confidence: 99%

“…The RAS system is a pathway that is importantly regulated by peroxisome proliferator-activated receptors (PPARs). PPARs belong to the nuclear family of ligand activated transcription factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ [ 7 ]., Our group had previously demonstrated the cardioprotective effects of PPAR-α stimulation (by fibrates) by reducing oxidative stress during myocardial ischemia [ 7 , 11 , 14 , 15 ]. Moreover, fenofibrate, a PPAR-α agonist, is beneficial in MetS, type 2 diabetes and cardiovascular diseases [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II

Ibarra-Lara¹,

Sánchez-Aguilar²,

Sánchez-Mendoza³

et al. 2016

Molecules

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Renin-angiotensin system (RAS) activation promotes oxidative stress which increases the risk of cardiac dysfunction in metabolic syndrome (MetS) and favors local insulin resistance. Fibrates regulate RAS improving MetS, type-2 diabetes and cardiovascular diseases. We studied the effect of fenofibrate treatment on the myocardic signaling pathway of Angiotensin II (Ang II)/Angiotensin II type 1 receptor (AT1) and its relationship with oxidative stress and myocardial insulin resistance in MetS rats under heart ischemia. Control and MetS rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); and (c) fenofibrate-treated myocardial infarction (MI-F). Treatment with fenofibrate significantly reduced triglycerides, non-high density lipoprotein cholesterol (non-HDL-C), insulin levels and insulin resistance index (HOMA-IR) in MetS animals. MetS and MI increased Ang II concentration and AT1 expression, favored myocardial oxidative stress (high levels of malondialdehyde, overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), decreased total antioxidant capacity and diminished expression of superoxide dismutase (SOD)1, SOD2 and catalase) and inhibited expression of the insulin signaling cascade: phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PkB, also known as Akt)/Glut-4/endothelial nitric oxide synthase (eNOS). In conclusion, fenofibrate treatment favors an antioxidant environment as a consequence of a reduction of the Ang II/AT1/NOX4 signaling pathway, reestablishing the cardiac insulin signaling pathway. This might optimize cardiac metabolism and improve the vasodilator function during myocardial ischemia.

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Section: Discussionmentioning

confidence: 99%

“…TAC was determined following the method as previously reported by Ibarra-Lara et al [ 15 ] based on the reduction of Cu 2+ to Cu 1+ .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II

Ibarra-Lara¹,

Sánchez-Aguilar²,

Sánchez-Mendoza³

et al. 2016

Molecules

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“…PPARα has been suggested to affect the signaling pathway of RAS (Banks and Oyekan, 2008 ; Ibarra-Lara et al, 2010 ). Stimulation of PPARα with clofibrate favored ACE2/Ang-(1–7)/ATR2 axis in aortic coarctation-induced hypertensive rats as evidenced by enhancing Ang-(1-7) and ACE2 expression in the heart (Ibarra-Lara et al, 2016 ). Recent studies found that H 2 S promoted the activation of PPARγ in macrophages (Zhang et al, 2012 ) and facilitated the nuclear translocation of PPARα in fat-fed apoE −/− mice, thus exerting beneficial effect on atherogenesis (Li et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Attenuates Atherosclerosis in a Partially Ligated Carotid Artery Mouse model via Regulating Angiotensin Converting Enzyme 2 Expression

et al. 2017

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Hydrogen sulfide has been suggested to play an essential role in atherogenesis. There is a paucity of information about the association between H2S and angiotensin converting enzyme 2 (ACE2), a novel homolog of ACE. Therefore, the aim of the study was to explore the role of H2S in atherosclerosis with respect to ACE2 both in vitro and in vivo. Here, a murine model of acutely disturbed flow-induced atherosclerosis by left common carotid artery (LCA) partial ligation was utilized. We found that carotid partial ligation in high-fat fed apoE−/− mice significantly inhibited endogenous H2S synthesis in LCA. Application of NaHS, an H2S donor considerably attenuated the severity of atherosclerosis with upregulating carotid expression of ACE2, thus converting pro-atherosclerotic angiotensin II (Ang II) to anti-atherosclerotic angiotensin 1-7 (Ang-(1-7)). The anti-atherosclerotic effect of NaHS was dramatically abolished by treatment with MLN-4760, an ACE2 inhibitor. In contrast, blockage of H2S formation by DL-propargylglycine exacerbated the burden of atherosclerotic plaques accompanied by inhibiting carotid expression of ACE2. At the cellular level, NaHS dose-dependently promoted the expression of ACE2 and conversion from Ang II to Ang-(1-7) in unstimulated or LPS-stimulated endothelial cells, thus exerting anti-inflammatory properties. The anti-inflammatory effect of NaHS was abrogated by pretreatment with DX600, a selective ACE2 inhibitor. In conclusion, these data provide direct evidences that endogenous H2S insufficiency exists in acute flow disturbance-induced atherosclerosis and that application of H2S may protect against atherosclerosis via upregulating ACE2 expression in endothelial cells.

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Molecular mechanisms and therapeutic perspectives of peroxisome proliferator‐activated receptor α agonists in cardiovascular health and disease

Cheng

Zhang

et al. 2023

Medicinal Research Reviews

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The prevalence of cardiovascular disease (CVD) has been rising due to sedentary lifestyles and unhealthy dietary patterns. Peroxisome proliferator‐activated receptor α (PPARα) is a nuclear receptor regulating multiple biological processes, such as lipid metabolism and inflammatory response critical to cardiovascular homeostasis. Healthy endothelial cells (ECs) lining the lumen of blood vessels maintains vascular homeostasis, where endothelial dysfunction associated with increased oxidative stress and inflammation triggers the pathogenesis of CVD. PPARα activation decreases endothelial inflammation and senescence, contributing to improved vascular function and reduced risk of atherosclerosis. Phenotypic switch and inflammation of vascular smooth muscle cells (VSMCs) exacerbate vascular dysfunction and atherogenesis, in which PPARα activation improves VSMC homeostasis. Different immune cells participate in the progression of vascular inflammation and atherosclerosis. PPARα in immune cells plays a critical role in immunological events, such as monocyte/macrophage adhesion and infiltration, macrophage polarization, dendritic cell (DC) embedment, T cell activation, and B cell differentiation. Cardiomyocyte dysfunction, a major risk factor for heart failure, can also be alleviated by PPARα activation through maintaining cardiac mitochondrial stability and inhibiting cardiac lipid accumulation, oxidative stress, inflammation, and fibrosis. This review discusses the current understanding and future perspectives on the role of PPARα in the regulation of the cardiovascular system as well as the clinical application of PPARα ligands.

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Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle

Cited by 18 publications

References 29 publications

Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II

Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II

Hydrogen Sulfide Attenuates Atherosclerosis in a Partially Ligated Carotid Artery Mouse model via Regulating Angiotensin Converting Enzyme 2 Expression

Molecular mechanisms and therapeutic perspectives of peroxisome proliferator‐activated receptor α agonists in cardiovascular health and disease

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