Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats
BackgroundInflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4) plays an important role in pathogenesis of cardiac diseases....
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Frontiers Media S.A.
2017-06-01
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Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00719/full |
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author | Parmeshwar B. Katare Pankaj K. Bagul Amit K. Dinda Sanjay K. Banerjee |
author_facet | Parmeshwar B. Katare Pankaj K. Bagul Amit K. Dinda Sanjay K. Banerjee |
author_sort | Parmeshwar B. Katare |
collection | DOAJ |
description | BackgroundInflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4) plays an important role in pathogenesis of cardiac diseases. Being an important regulator of innate immunity, the precise pathway of TLR4-mediated cardiac complications is yet to be established. Therefore, the primary objective of the present study was to find the role of TLR4 in cardiac hypertrophy and the molecular mechanism thereof.MethodsCardiac hypertrophy was induced with administration of isoproterenol (5 mg/kg/day, sc). TLR4 receptor inhibitor RS-LPS (lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides; 5 μg/day) and agonist lipopolysaccharide (LPS) (from Escherichia coli; 3.12 μg/day) were administered through osmotic pump along with isoproterenol. Cardiac hypertrophy as well as oxidative stress and mitochondrial parameters were evaluated.ResultsCardiac hypertrophy was confirmed with increased heart weight/body weight ratio as well as assessment of hypertrophic markers in heart. There was a marked increase in the TLR4 expression and oxidative stress along with mitochondrial dysfunction in ISO group. TLR4 inhibition significantly decreased heart weight/body weight ratio and ANP, collagen, and β-MHC expression and restored the disturbed cellular antioxidant flux. The mitochondrial perturbations that were observed in hypertrophy heart was normalized after administration of TLR4 inhibitor but not with the agonist. TLR4 agonism further exaggerated the oxidative stress in heart and hence accelerated the disease development and progression.ConclusionOur data show that increased TLR4 ligand pool in cardiac hypertrophy may exaggerate the disease progression. However, inhibition of TLR4 attenuated cardiac hypertrophy through reduced cardiac redox imbalance and mitochondrial dysfunction. |
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spelling | doaj.art-14c56447609c44fa9b729ad02feb37c32022-12-22T03:52:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-06-01810.3389/fimmu.2017.00719272352Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in RatsParmeshwar B. Katare0Pankaj K. Bagul1Amit K. Dinda2Sanjay K. Banerjee3Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, IndiaDrug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, IndiaDepartment of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, IndiaDrug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, IndiaBackgroundInflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4) plays an important role in pathogenesis of cardiac diseases. Being an important regulator of innate immunity, the precise pathway of TLR4-mediated cardiac complications is yet to be established. Therefore, the primary objective of the present study was to find the role of TLR4 in cardiac hypertrophy and the molecular mechanism thereof.MethodsCardiac hypertrophy was induced with administration of isoproterenol (5 mg/kg/day, sc). TLR4 receptor inhibitor RS-LPS (lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides; 5 μg/day) and agonist lipopolysaccharide (LPS) (from Escherichia coli; 3.12 μg/day) were administered through osmotic pump along with isoproterenol. Cardiac hypertrophy as well as oxidative stress and mitochondrial parameters were evaluated.ResultsCardiac hypertrophy was confirmed with increased heart weight/body weight ratio as well as assessment of hypertrophic markers in heart. There was a marked increase in the TLR4 expression and oxidative stress along with mitochondrial dysfunction in ISO group. TLR4 inhibition significantly decreased heart weight/body weight ratio and ANP, collagen, and β-MHC expression and restored the disturbed cellular antioxidant flux. The mitochondrial perturbations that were observed in hypertrophy heart was normalized after administration of TLR4 inhibitor but not with the agonist. TLR4 agonism further exaggerated the oxidative stress in heart and hence accelerated the disease development and progression.ConclusionOur data show that increased TLR4 ligand pool in cardiac hypertrophy may exaggerate the disease progression. However, inhibition of TLR4 attenuated cardiac hypertrophy through reduced cardiac redox imbalance and mitochondrial dysfunction.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00719/fullcardiac hypertrophyisoproterenoltoll-like receptor 4lipopolysaccharideRS-LPSoxidative phosphorylation |
spellingShingle | Parmeshwar B. Katare Pankaj K. Bagul Amit K. Dinda Sanjay K. Banerjee Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats Frontiers in Immunology cardiac hypertrophy isoproterenol toll-like receptor 4 lipopolysaccharide RS-LPS oxidative phosphorylation |
title | Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats |
title_full | Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats |
title_fullStr | Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats |
title_full_unstemmed | Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats |
title_short | Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats |
title_sort | toll like receptor 4 inhibition improves oxidative stress and mitochondrial health in isoproterenol induced cardiac hypertrophy in rats |
topic | cardiac hypertrophy isoproterenol toll-like receptor 4 lipopolysaccharide RS-LPS oxidative phosphorylation |
url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00719/full |
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