Abstract 61: miRNA-21 Targets Left Ventricular Peroxisome Proliferator-activated Receptor Alpha in a Rat Model of Type 4 Cardiorenal Syndrome

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alison J Kriegel ◽  
Mingyu Liang ◽  
Yong Liu ◽  
Pengyuan Liu ◽  
Allen W Cowley ◽  
...  
Keyword(s):  
Protein Expression ◽  
Rat Model ◽  
Molecular Mechanisms ◽  
Cardiorenal Syndrome ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiac Pathology ◽  
Receptor Alpha

Type 4 cardiorenal syndrome (CRS4) is a condition in which chronic kidney disease (CKD) contributes to cardiovascular pathology including cardiac dysfunction, left ventricular (LV) hypertrophy, atherosclerosis, and heart failure. We have used a rat model of CKD, the 5/6 nephrectomy (5/6 NX), to study molecular mechanisms that mediate the development of cardiac pathology in CRS4. We previously reported that the upregulation of microRNA miR-21-5p (miR-21) in the left ventricle (LV) was accompanied by pathological remodeling and a drop in fractional shortening in adult male Sprague Dawley rats 7 weeks after 5/6 NX. Systemic knockdown of miR-21 in 5/6 NX rats with LNA-modified anti-miR-21 improved cardiac function, however it did not reduce the modest fibrosis observed with our 5/6 NX model or upregulate miR-21 targets identified in other models of cardiac pathology, suggesting a novel cardiac target for miR-21 in this model. Through next-generation mRNA sequencing of LV tissues from anti-miR-21 treated rats, and subsequent Ingenuity Pathway Analysis, we have found cardioprotective alterations in genes related to cardiac hypertrophy, metabolism, immune and inflammatory signaling, and atherosclerosis. Suppression or reduction of miR-21 target peroxisome proliferator-activated receptor alpha (PPARa), a master regulator of fatty acid oxidation, has been reported to be involved in all of these processes. Translational suppression of PPARa through miR-21 has been confirmed in other tissues, but not in the myocardium. The average LV PPARa protein expression level was significantly reduced (-37.7 ± 5.4%) in the 5/6 NX model and restored by miR-21 knockdown (Western blot; n=5-6/group; mean ± SEM). Immunohistochemistry revealed that the pronounced alterations in PPARa expression occurred within cardiomyocytes (CMs) in these samples. Transfection of neonatal CMs with pre-miR-21, significantly reduced PPARa protein expression within 48 hours (-23.0 ± 0.9%; n=3/group). These data indicate that PPARa suppression by miR-21 occurs within LV in 5/6 NX model of CKD and that miR-21 can regulate PPARa in CMs. This regulation may be relevant in other models of chronic cardiac disease where increased miR-21 and suppression of PPARa have been independently reported.

scholarly journals PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

2017 ◽  
Vol 312 (2) ◽  
pp. H239-H249 ◽  
Author(s):  
Stephen W. Standage ◽  
Brock G. Bennion ◽  
Taft O. Knowles ◽  
Dolena R. Ledee ◽  
Michael A. Portman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Mouse Models ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Regulatory State ◽  
Peroxisome Proliferator Activated Receptor

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα ( Ppara−/−) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara−/− mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara−/− mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara−/− mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.

Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator

2002 ◽  
Vol 283 (3) ◽  
pp. H949-H957 ◽  
Author(s):  
Ellen Aasum ◽  
Darrell D. Belke ◽  
David L. Severson ◽  
Rudolph A. Riemersma ◽  
Marie Cooper ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Cardiac Metabolism ◽  
Left Ventricular ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Hearts from diabetic db/ db mice, a model of Type 2 diabetes, exhibit left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-α (PPAR-α) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/ db mice. Consequently, the effect of 4- to 5-wk treatment of db/ db mice with a novel PPAR-α ligand (BM 17.0744; 25–38 mg · kg−1 · day−1), commencing at 8 wk of age, on ex vivo cardiac function and metabolism was determined. Elevated plasma concentrations of glucose, fatty acids, and triacylglycerol (34.0 ± 3.6, 2.0 ± 0.4, and 0.9 ± 0.1 mM, respectively) were reduced to normal after treatment with BM 17.0744 (10.8 ± 0.6, 1.1 ± 0.1, and 0.6 ± 0.1 mM). Plasma insulin was also reduced significantly in treated compared with untreated db/ db mice. Chronic treatment of db/ db mice with the PPAR-α agonist resulted in a 50% reduction in rates of fatty acid oxidation, with a concomitant increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold). Correction of the diabetes-induced abnormalities in systemic and cardiac metabolism after BM 17.0744 treatment did not, however, improve left ventricular contractile function.

scholarly journals Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

1999 ◽  
Vol 22 (1) ◽  
pp. 1-8 ◽  
Author(s):  
PR Holden ◽  
JD Tugwood
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Species Differences ◽  
Plasma Cholesterol ◽  
Specific Gene ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apparent Lack ◽  
Receptor Alpha ◽  
Rats And Mice

Peroxisome proliferators (PPs) are chemicals of industrial and pharmaceutical importance that elicit liver carcinogenesis by a non-genotoxic mechanism. One of the intriguing properties of PPs is that the pleiotropic effects of these compounds (including increased DNA synthesis and peroxisome proliferation) are seen in rats and mice only, but not humans. It is important to determine the risks to humans of environmental and therapeutic exposure to these compounds by understanding the mechanisms of non-genotoxic hepatocarcinogenesis in rodents. To understand this apparent lack of human susceptibility, attention has focused on the peroxisome proliferator-activated receptor alpha (PPARalpha), which appears to mediate the effects of PPs in rodents. It is also known to mediate the hypolipidaemic effects that fibrate drugs exert on humans with elevated plasma cholesterol and triglyceride levels. Human PPARalphas share many functional characteristics with the rodent receptors, in that they can be transcriptionally activated by PPs and regulate specific gene expression. However, one key difference is that PPARalpha is less abundant in human than in rodent liver, which has led to the suggestion that species differences result from quantitative differences in gene expression. In this review we describe the effects of PPs and what is known of the molecular mechanisms of action and species differences with respect to rodents and man. Attention will be given to differences in the amounts of PPARalpha between species as well as the 'qualitative' aspects of PPARalpha-mediated gene regulation which might also explain the activation of some genes and not of others in human liver by PPs.

Platycodin D Protects Human Fibroblast Cells from Premature Senescence Induced by H2O2 through Improving Mitochondrial Biogenesis

Pharmacology ◽  
2020 ◽  
Vol 105 (9-10) ◽  
pp. 598-608 ◽  
Author(s):  
Chenyang Shi ◽  
Qin Li ◽  
Xinyue Zhang
Keyword(s):  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Molecular Mechanisms ◽  
Enzyme Linked Immunosorbent Assay ◽  
Peroxisome Proliferator ◽  
Premature Senescence ◽  
Peroxisome Proliferator Activated Receptor ◽  
Platycodin D ◽  
Therapeutic Benefits

<b><i>Background:</i></b> Although Platycodin D (PLD) is the main active saponin of <i>Platycodon grandiflorum</i> (PG) and responsible for multiple therapeutic benefits, including antioxidant and antiaging, only few direct demonstrations have been reported on the role of PLD in antiaging process. The present investigation was carried out to elucidate the protection of PLD against aging in vitro and associated molecular mechanisms on H<sub>2</sub>O<sub>2</sub>-induced premature senescence model in human ­fetal lung diploid fibroblasts 2BS cells. <b><i>Methods:</i></b> The cellular morphology, cell cycle, and senescence-associated β-galactosidase activity assays were used for senescence-like phenotypes determination in the oxidant challenged model. The oxygen-free radicals reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA) determinations were estimated by enzyme-linked immunosorbent assay assay. The potential of the mitochondria mass and the mitochondrial membrane were used to observe the alteration of mitochondria. Western blot analysis was performed to determine the protein expression. <b><i>Results:</i></b> The results showed that PLD significantly reversed senescence-like phenotypes in the oxidant challenged model, as well as related molecules expression such as p53, p21, and p16. Moreover, PLD treatment significantly decreased the levels of ROS, 4-HNE, and MDA in H<sub>2</sub>O<sub>2</sub>-treated 2BS cells. The mechanisms responsible for the antioxidant and antiaging effects of PLD were investigated, we found that mitochondria under PLD conditions show increase membrane potential ratio and stimulate the proliferation of mitochondria mass. In addition, the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α and its downstream targets, that is, nuclear respiratory factor and mitochondrial transcription factor A were also increased in mitochondrial biogenesis. <b><i>Conclusion:</i></b> These results indicated that PLD prevented H<sub>2</sub>O<sub>2</sub>-induced premature senescence in vitro by improving mitochondrial biogenesis to attenuate age-dependent endogenous oxidative damage. <b><i>Key Message:</i></b> The study revealed the antioxidant and antiaging potential of PLD against H<sub>2</sub>O<sub>2</sub>-induced premature senescence.

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