scholarly journals Downregulation of PPARα during Experimental Left Ventricular Hypertrophy is Critically Dependent on Nox2 NADPH Oxidase Signalling

2020 ◽  
Vol 21 (12) ◽  
pp. 4406
Author(s):  
Adam P. Harvey ◽  
Emma Robinson ◽  
Kevin S. Edgar ◽  
Ross McMullan ◽  
Karla M. O’Neill ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Systolic Dysfunction ◽  
Reactive Oxygen Species Generation ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Altered Expression

Pressure overload-induced left ventricular hypertrophy (LVH) is initially adaptive but ultimately promotes systolic dysfunction and chronic heart failure. Whilst underlying pathways are incompletely understood, increased reactive oxygen species generation from Nox2 NADPH oxidases, and metabolic remodelling, largely driven by PPARα downregulation, are separately implicated. Here, we investigated interaction between the two as a key regulator of LVH using in vitro, in vivo and transcriptomic approaches. Phenylephrine-induced H9c2 cardiomyoblast hypertrophy was associated with reduced PPARα expression and increased Nox2 expression and activity. Pressure overload-induced LVH and systolic dysfunction induced in wild-type mice by transverse aortic constriction (TAC) for 7 days, in association with Nox2 upregulation and PPARα downregulation, was enhanced in PPARα−/− mice and prevented in Nox2−/− mice. Detailed transcriptomic analysis revealed significantly altered expression of genes relating to PPARα, oxidative stress and hypertrophy pathways in wild-type hearts, which were unaltered in Nox2−/− hearts, whilst oxidative stress pathways remained dysregulated in PPARα−/− hearts following TAC. Network analysis indicated that Nox2 was essential for PPARα downregulation in this setting and identified preferential inflammatory pathway modulation and candidate cytokines as upstream Nox2-sensitive regulators of PPARα signalling. Together, these data suggest that Nox2 is a critical driver of PPARα downregulation leading to maladaptive LVH.

Abstract 15453: CaMKII Plays a Critical Role in Pressure Overload-Induced Left Ventricular Hypertrophy by Modulating Foxp1 Expression

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Runming Jin ◽  
Lei Chen ◽  
Anweshan Samanta ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Specific Binding ◽  
Critical Role ◽  
Nodal Point ◽  
Pressure Overload ◽  
Promoter Sequence ◽  
Left Ventricular ◽  
Hypertrophic Response

Introduction: The necessity of IL-6 signaling in pressure overload-induced left ventricular hypertrophy remains controversial. Whether Calcium/calmodulin-dependent kinase II (CaMKII) participates in IL-6-induced and pressure overload-induced hypertrophic signaling remains unknown. Hypothesis: CaMKII acts as a nodal point for integrating IL-6 signaling in pressure overload induced hypertrophic molecular pathways. Methods and Results: In vitro, exposure to IL-6 for 24 h induced hypertrophy in H9c2 cells. This hypertrophic response was associated with robust increase in phospho-CaMKII levels in IL-6-treated cells, and accompanied by increase in myocyte hypertrophy markers. Interestingly, Mef2a levels also increased, and this was associated with reduced Foxp1 expression, which has Mef2a specific binding site at CTAAAAATAG (-401 ~ -391) in Foxp1 promoter sequence. These effects were inhibited by selective CaMKII inhibitor KN-62. Next, we performed transverse aortic constriction (TAC) in IL-6-/- mice and wild-type (WT) C57BL/6J mice to induce hypertrophy. After 6 wks, TAC-induced hypertrophy was significantly attenuated in IL-6-/- mice compared with WT mice, documented by necropsy findings, echocardiography, and LV morphometry. Phospho-CaMKII levels increased significantly in control mouse hearts at 2 wks after TAC, while this increase was significantly blunted in IL-6-/- hearts (Figure). Moreover, and consistent with attenuated CaMKII activity, the expression of Mef2a was lower and expression of Foxp1 was higher in IL-6-/- hearts after TAC compared with controls. Conclusions: We identify a novel signaling module whereby regulation of Foxp1 by CaMKII plays a critical role in pressure overload-induced and IL-6-mediated cardiac hypertrophy. These molecular insights may lead to formulation of novel therapeutic agents for LV hypertrophy and dysfunction.

scholarly journals Cardiomyocyte loss is not required for the progression of left ventricular hypertrophy induced by pressure overload in female mice

2016 ◽  
Vol 229 (1) ◽  
pp. 75-81 ◽  
Author(s):  
Julia Schipke ◽  
Clara Grimm ◽  
Georg Arnstein ◽  
Jens Kockskämper ◽  
Simon Sedej ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Female Mice

Role of Calcineurin-Dependent Signaling Pathway on the Left Ventricular Hypertrophy Induced by Pressure Overload

2001 ◽  
Vol 31 (11) ◽  
pp. 1159
Author(s):  
Hainan Piao ◽  
Jin Sook Kwon ◽  
Hye Young Lee ◽  
Tae Jin Youn ◽  
Dong Woon Kim ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Signaling Pathway ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Dependent Signaling Pathway

39 Pressure-overload left ventricular hypertrophy in the rat

1993 ◽  
Vol 11 (11) ◽  
pp. 1314
Author(s):  
J. F. Viallard ◽  
P. Dos-Santos ◽  
G. Raffard ◽  
L. Tariosse ◽  
G. Gouverneur ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular

scholarly journals Left ventricular hypertrophy in patients treated with regular hemodialyses

2008 ◽  
Vol 61 (7-8) ◽  
pp. 369-374 ◽  
Author(s):  
Dejan Petrovic ◽  
Biljana Stojimirovic
Keyword(s):  
Risk Factors ◽  
Left Ventricle ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiovascular Morbidity ◽  
Morbidity And Mortality ◽  
Concentric Hypertrophy ◽  
Cardiovascular Morbidity And Mortality

Left ventricular hypertrophy is the main risk factor for development of cardiovascular morbidity and mortality in patients on hemodialysis. Left ventricular hypertrophy is found in 75% of the patients treated with hemodialysis. Risk factors for left ventricular hypertrophy in patients on hemodialysis include: blood flow through arterial-venous fistula, anemia, hypertension, increased extracellular fluid volume, oxidative stress, microinflammation, hyperhomocysteinemia, secondary hyperpara- thyroidism, and disturbed calcium and phosphate homeostasis. Left ventricular pressure overload leads to parallel placement of new sarcomeres and development of concentric hypertrophy of left ventricle. Left ventricular hypertrophy advances in two stages. In the stage of adaptation, left ventricular hypertrophy occurs as a response to increased tension stress of the left ventricular wall and its action is protective. When volume and pressure overload the left ventricle chronically and without control, adaptive hypertrophy becomes maladaptive hypertrophy of the left ventricle, where myocytes are lost, systolic function is deranged and heart insufficiency is developed. Left ventricular mass index-LVMi greater than 131 g/m2 in men and greater than 100 g/m2 in women, and relative wall thickness of the left ventricle above 0.45 indicate concentric hypertrophy of the left ventricle. Eccentric hypertrophy of the left ventricle is defined echocardiographically as LVMi above 131 g/m2 in men and greater than 100 g/m2 in women, with RWT ?0.45. Identification of patients with increased risk for development of left ventricular hypertrophy and application of appropriate therapy to attain target values of risk factors lead to regression of left ventricular hypertrophy, reduced cardiovascular morbidity and mortality rates and improved quality of life in patients treated with regular hemodialyses.

Abstract 1582: Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on Pressure Overloaded-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Zhongbing Lu ◽  
John Fassett ◽  
Xin Xu ◽  
Xinli Hu ◽  
Guangshuo Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Heart Association ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Extracellular Adenosine ◽  
Myocardial Oxidative Stress

Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A 1 receptors (A 1 R) and A 3 receptors(A 3 R) is not known. To test the hypothesis A 1 R and A 3 R can protect the heart against systolic overload, we exposed A 3 R gene deficient (A 3 R KO) mice and A 1 R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A 3 R KO attenuated 5 weeks TAC-induced left ventricular (LV) hypertrophy (ratio of ventricular mass/body weight increased to 7.6 ±0.3 mg/g in wild type (Wt) mice as compared with 6.3±0.4 mg/g in KO), fibrosis and dysfunction (LV ejection fraction decreased to 43±2.5% and 55±4.2% in Wt and KO mice, respectively). A 3 R KO also attenuated the TAC-induced increases of myocardial ANP and the oxidative stress markers 3-nitrotyrosine(3-NT ) and 4-hydroxynonenal. In addition, A 3 R KO significantly attenuated TAC-induced activation of multiple MAP kinase pathways, and the activation of Akt-GSK signaling pathway. In contrast, A 1 R-KO increased TAC-induced mortality, but did not alter ventricular hypertrophy or dysfunction compared to Wt mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction, and increased myocardial 3-NT, indicates that extracellular adenosine protects heart against TAC-induced ventricular oxidative stress and hypertrophy. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine (CADO) reduced cell area, protein synthesis, ANP and 3-NT. Antagonism of A3R significantly potentiated the anti-hypertrophic effects of CADO. Our data demonstrated that extracellular adenosine exerts protective effects on the overloaded heart, but A 3 R act counter to the protective effect of adenosine. The data suggest that selective attenuation of A 3 R activity might be a novel approach to attenuate pressure overload-induced myocardial oxidative stress, LV hypertrophy and dysfunction. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

scholarly journals A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial

2019 ◽  
Vol 40 (41) ◽  
pp. 3409-3417 ◽  
Author(s):  
Mohapradeep Mohan ◽  
Shaween Al-Talabany ◽  
Angela McKinnie ◽  
Ify R Mordi ◽  
Jagdeep S S Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery Disease ◽  
Body Weight ◽  
Coronary Artery ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Haemoglobin A1c ◽  
Metformin Treatment ◽  
Artery Disease

Abstract Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

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