scholarly journals Catalase Mediates the Inhibitory Actions of PPARδ against Angiotensin II-Triggered Hypertrophy in H9c2 Cardiomyocytes

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1223
Author(s):  
Jung Seok Hwang ◽  
Jinwoo Hur ◽  
Won Jin Lee ◽  
Jun Pil Won ◽  
Hyuk Gyoon Lee ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Natriuretic Peptide ◽  
Wall Stress ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
H9c2 Cardiomyocytes

Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor δ (PPARδ) is involved in the anti-hypertrophic activity of PPARδ in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPARδ by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPARδ, indicating that PPARδ mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPARδ significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPARδ also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPARδ on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPARδ are mediated through catalase induction. Furthermore, GW501516-activated PPARδ exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPARδ may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.

scholarly journals Peroxisome Proliferator Activated Receptor-αAgonist Slows the Progression of Hypertension, Attenuates Plasma Interleukin-6 Levels and Renal Inflammatory Markers in Angiotensin II Infused Mice

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Justin L. Wilson ◽  
Rong Duan ◽  
Ahmed El-Marakby ◽  
Abdulmohsin Alhashim ◽  
Dexter L. Lee
Keyword(s):  
Angiotensin Ii ◽  
Inflammatory Markers ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Induced Hypertension ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Renal Expression

The anti-inflammatory properties of PPAR-αplays an important role in attenuating hypertension. The current study determines the anti-hypertensive and anti-inflammatory role of PPAR-αagonist during a slow-pressor dose of Ang II (400 ng/kg/min). Ten to twelve week old male PPAR-αKO mice and their WT controls were implanted with telemetry devices and infused with Ang II for 12 days. On day 12 of Ang II infusion, MAP was elevated in PPAR-αKO mice compared to WT (161±4 mmHg versus145±4 mmHg) and fenofibrate (145 mg/kg/day) reduced MAP in WT + Ang II mice (134±7 mmHg). Plasma IL-6 levels were higher in PPAR-αKO mice on day 12 of Ang II infusion (30±4versus8±2 pg/mL) and fenofibrate reduced plasma IL-6 in Ang II-treated WT mice (10±3 pg/mL). Fenofibrate increased renal expression of CYP4A, restored renal CYP2J expression, reduced the elevation in renal ICAM-1, MCP-1 and COX-2 in WT + Ang II mice. Our results demonstrate that activation of PPAR-αattenuates Ang II-induced hypertension through up-regulation of CYP4A and CYP2J and an attenuation of inflammatory markers such as plasma IL-6, renal MCP-1, renal expression of ICAM-1 and COX-2.

Abstract P118: Angiotensin Ii Hypertension-dependent Decrease In Circadian Rhythms Of Cardiovascular Parameters: Role Of Peroxisome Proliferator Activated Receptor-α

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Dexter L Lee ◽  
Sheree M Johnson ◽  
Ian Stukes ◽  
Nia Williams ◽  
Ugoeze C Ananaba ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Circadian Rhythms ◽  
Diastolic Pressure ◽  
Interleukin 17 ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiovascular Parameters ◽  
Nitrite Nitrate

Decreases in circadian rhythms of cardiovascular parameters, such as day to night changes in mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), systolic (SP) and diastolic pressure (DP) are an index of cardiovascular disease. Peroxisome proliferator activated receptor - alpha (PPAR-α) has been shown to decrease inflammatory markers and hypertension a slow pressor dose of Angiotensin II (Ang II); however, the role of PPAR-α on cardiovascular parameters during the initial stages of Ang II infusion is unknown. We hypothesize that the absence of PPAR-α will cause a reduction in the day to night changes in MAP, HR, PP, SP and DP during the initial stages of a slow pressor dose of Ang II. Male (10 - 12 weeks old) PPAR-αknockout (KO) and wild-type (WT) mice were infused with Ang II (400 ng/kg/min) for three days. Radiotelemetry was used to measure the cardiovascular parameters. The baseline MAP values were: 100 + 10 mmHg (WT) and 108 + 9 mmHg for KO. The baseline HR values were: 530 + 10 bpm (WT) and 526 + 6 bpm (KO). The baseline PPs were 17 + 0.2 mmHg (WT) and 18 + 0.3 mmHg (KO). The baseline SBPs were 108 + 9 mmHg (WT) and 116 + 10 mmHg (KO). The baseline DBPs were 91 + 9 mmHg (WT) and 98 + 10 mmHg (KO). During the first three days of Ang II infusion, the change in day to night MAP was 20 ± 2 mmHg and 10 ± 2 mmHg in Ang II treated WT and KO mice, respectively. Changes in day to night HR were 25 ± 4 bpm and 46 ± 7 bpm for WT and KO mice, respectively. The day to night changes in PP were 8 ± 1 mmHg for WT and 2 ± 2 mmHg for KO mice. The day to night changes in SBPs were 20 ± 2 mmHg and 12 ± 3 mmHg for WT and KO mice, respectively. Changes in day to night DBPs were 18 ± 2 mmHg for WT and 9 ± 2 mmHg for KO mice. TBARS and Interleukin-17 were increased in heart homogenates of KO + Ang II (15 ± 2 μM) and (1.5 ± 0.3 ng/mL) vs WT + Ang II (11 ± 3 μM) and (1.0 ± 0.2 ng/mL). Nitrite/Nitrate was decreased in KO + Ang II (1.0 ± 0.1 nM) vs WT + Ang II (1.5 ± 0.5 nM). In summary, the absence of PPAR-α decreases the day to night changes in MAP, SBP, DBP and PP during the initial three days of a slow pressor dose of Ang II. In the absence of PPAR-α, increases in oxidative stress and inflammation are mechanisms that may contribute to the changes in the cardiovascular parameters and suggest the occurrence of cardiovascular diseases during a slow pressor dose of Ang II-infusion.

Abstract P268: The Effects of a Slow Pressor Dose of Angiotensin II on Sodium Transporters Expression in the Kidney Cortex are Independent of PPAR-alpha

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Syed J Khundmiri ◽  
Carolyn M Ecelbarger ◽  
Dexter L Lee
Keyword(s):  
Angiotensin Ii ◽  
Kidney Cortex ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Ppar Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sodium Transporters ◽  
Subunit Expression ◽  
Α1 Subunit

A slow pressor dose of Angiotensin II (Ang II) has been shown to increase the expression of sodium transporters in the proximal tubules (NHE3), TALH (NKCC2) and distal nephrons (NCC) of Sprague Dawley rats before an increase in blood pressure. Peroxisome Proliferator Activated Receptor - alpha (PPAR-alpha) has been shown to be involved in pressure natriuresis through changes in sodium transport via ameloride and thiazide-dependent mechanisms. We hypothesized that the changes in expression of the sodium transporters during Ang II hypertension were dependent upon PPAR-alpha expression. To address this hypothesis, we treated wild-type (WT) and PPAR-alpha knockout (KO) mice with a slow pressor dose of Ang II (400 ng/kg/min) for 12 days. Mean arterial pressure (MAP) was measured by radiotelemetry. Control MAP was not different between WT (110 ± 8 mmHg) and PPAR-alpha KO mice (112 ± 12 mmHg). On day 12 of Ang II, MAP for PPAR-alpha KO (156 ± 16) mice was significantly higher than WT (138 ± 11 mmHg) mice. The expression of NHE3, NHERF1, NKA-α1 subunit, NKCC2, and NCC was detected in kidney cortical homogenates by western blotting. Kidneys were homogenized and 25 μg of supernatant proteins were separated by 10% SDS-PAGE, transferred to nitrocellulose paper, and blotted against antibodies to NHE3, NHERF1, NKA α1 subunit, NKCC2, and NCC. The slow pressor dose of Ang II decreased the expression of NHE3 in WT + Ang II (0.14 ± 0.02 ODU) and PPAR-alpha KO + Ang II (0.10 ± 0.02 ODU), when compared to WT (2.61 ± 0.93 ODU) and PPAR-alpha KO (2.20 ± 0.58 ODU) controls. Ang II-treatment also decreased NKCC2 in both WT (0.31 ± 0.10 ODU) and PPAR-alpha KO (0.22 ± 0.03 ODU). Ang II hypertension caused similar decreases in NCC and NHERF1 expression in WT and PPAR-α KO mice. NKA alpha1 subunit expression was increased during Ang II hypertension in both WT (1.06 ± 0.26 ODU) and PPAR-α KO (1.64 ± 0.26 ODU) mice. Our results suggest that the effects of a slow pressor dose of Ang II on expression of sodium transporters are independent of PPAR-alpha expression. Future studies are needed to determine the effects of decreasing NHE3, NKCC2, NCC and NHERF1 expression in the kidney on urinary salt excretion during a slow pressor dose of Ang II.

scholarly journals The anti-adipogenic effect of angiotensin II on human preadipose cells involves ERK1,2 activation and PPARG phosphorylation

2010 ◽  
Vol 206 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Paula Fuentes ◽  
María José Acuña ◽  
Mariana Cifuentes ◽  
Cecilia V Rojas
Keyword(s):  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Current Knowledge ◽  
Adipogenic Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fat Depots ◽  
Adipogenic Effect

Despite the importance of adipocyte formation for adipose tissue physiology, current knowledge about the mechanisms that regulate the recruitment of progenitor cells to undergo adipogenic differentiation is limited. A role for locally generated angiotensin II emerged from studies with human and murine cells. Preadipose cells from different human fat depots show reduced response to adipogenic stimuli when exposed to angiotensin II. This investigation sought to gain an insight into the intracellular mechanisms involved in the anti-adipogenic response of human preadipose cells from omental fat to angiotensin II. Its effect was evaluated on cells stimulated to adipogenic differentiation in vitro, by assessment of glycerol-3-phosphate dehydrogenase activity and expression of early markers of adipogenesis. Extracellular signal-regulated kinase1,2 (ERK1,2) pathway activation was inferred from the phosphorylated to total ERK1,2 ratio determined by western blot. Exposure to angiotensin II throughout the 10-day differentiation period resulted in a reduced adipogenic response. A similar anti-adipogenic effect was observed when this hormone was present during the first 48 h of induction to differentiation. Angiotensin II treatment had no consequences on CCAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ (PPARG) induction, but increased the phosphorylated form of the key adipogenic regulator PPARG. Upon angiotensin II exposure, a raise of phosphorylated ERK1,2 was determined, which was more prominent 8–20 h after induction of adipogenesis (when controls reached negligible values). Chemical inhibition of ERK1,2 phosphorylation prevented angiotensin II-dependent reduction in adipogenesis. These results support the participation of the mitogen-activated protein kinase/ERK1,2 pathway in the anti-adipogenic effect of angiotensin II on preadipose cells from human omental adipose tissue.

Abstract 126: Peroxisomal Proliferator Activated Receptor Alpha Overexpression in Hypertrophied Cardiomyocytes Restores Mitochondrial Integrity and Function

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Santanu Rana
Keyword(s):  
Energy Demand ◽  
Cardiac Tissue ◽  
Structural Integrity ◽  
Heart Function ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Production ◽  
Receptor Alpha ◽  
And Function

Cardiac tissue engineering is an interdisciplinary field that engineers modulation of viable molecular milieu to restore, maintain or improve heart function. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux to maintain specialized cellular processes, yet the heart has a limited capacity for substrate storage and utilization during pathophysiological conditions. Damage to heart muscle, acute or chronic, leads to dysregulation of cardiac metabolic processes associated with gradual but progressive decline in mitochondrial respiratory pathways resulting in diminished ATP production. The Peroxisome Proliferator Activated Receptor Alpha ( PPARα ) is known to regulate fatty acid to glucose metabolic balance as well as mitochondrial structural integrity. In this study, a non-canonical pathway of PPARα was analyzed by cardiomyocyte targeted PPARα overexpression during cardiac hypertrophy that showed significant downregulation in p53 acetylation as well as GSK3β activation levels. Targeted PPARα overexpression during hypertrophy resulted in restoration of mitochondrial structure and function along with significantly improved mitochondrial ROS generation and membrane potential. This is the first report of myocyte targeted PPARα overexpression in hypertrophied myocardium that results in an engineered heart with significantly improved function with increased muscle mitochondrial endurance and reduced mitochondrial apoptotic load, thus conferring a greater resistance to pathological stimuli within cardiac microenvironment.

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