Different roles of BAG3 in cardiac physiological hypertrophy and pathological remodeling

Swim-training exercise in mice leads to cardiac remodeling associated with an improvement in contractile function. Protein O-linked N-acetylglucosamine ( O-GlcNAcylation) is a posttranslational modification of serine and threonine residues capable of altering protein-protein interactions affecting gene transcription, cell signaling pathways, and general cell physiology. Increased levels of protein O-GlcNAcylation in the heart have been associated with pathological conditions such as diabetes, ischemia, and hypertrophic heart failure. In contrast, the impact of physiological exercise on protein O-GlcNAcylation in the heart is currently unknown. Swim-training exercise in mice was associated with the development of a physiological hypertrophy characterized by an improvement in contractile function relative to sedentary mice. General protein O-GlcNAcylation was significantly decreased in swim-exercised mice. This effect was mirrored in the level of O-GlcNAcylation of individual proteins such as SP1. The decrease in protein O-GlcNAcylation was associated with a decrease in the expression of O-GlcNAc transferase (OGT) and glutamine-fructose amidotransferase (GFAT) 2 mRNA. O-GlcNAcase (OGA) activity was actually lower in swim-trained than sedentary hearts, suggesting that it did not contribute to the decreased protein O-GlcNAcylation. Thus it appears that exercise-induced physiological hypertrophy is associated with a decrease in protein O-GlcNAcylation, which could potentially contribute to changes in gene expression and other physiological changes associated with exercise.

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Abstract 151: A Novel Role for DDiT4L in Regulation of mTOR and Autophagy in the Heart

Circulation Research ◽

10.1161/res.113.suppl_1.a151 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Bridget Simonson ◽

Hannabeth Franchino ◽

Ashley Knight ◽

Anthony Rosenzweig ◽

Saumya Das

Keyword(s):

Heart Failure ◽

Protein Expression ◽

Glucose Deprivation ◽

Mtor Signaling ◽

Confocal Imaging ◽

Negative Regulator ◽

Neonatal Rat ◽

Pathological Hypertrophy ◽

Gene And Protein Expression ◽

Physiological Hypertrophy

Introduction: DDiT4L is a known negative regulator of mTOR signaling in skeletal muscle; however its role in the heart is unknown. We have recently showed increased DDiT4L mRNA in a murine transgenic model of pathological but not physiological hypertrophy. Here we test the hypothesis that DDiT4L is a regulator of mTOR signaling in the heart and may play a role in pathological hypertrophy and heart failure. Methods: We investigated the regulation of DDiT4L in murine models of hypertrophy and in cultured neonatal rat ventricular cardiomyocytes (NRVMs). Loss and gain of function of DDiT4L in mTOR regulation and autophagy was investigated using confocal imaging, immunoblotting, and qRT-PCR in NRVMs. Results: DDiT4L gene and protein expression was increased four-fold in pressure overload hypertrophy (n = 4-6, p<0.001), but not in a swim model of physiological hypertrophy. DDiT4L gene expression also significantly increased in a genetic model of dilated cardiomyopathy model (n = 4, p<0.001). In NRVMs, DDiT4L was induced by cardiac stressors such as pathological stretch, hypoxia, and glucose deprivation (n = 3-5 in duplicate, p<0.05-0.01). Increased DDiT4L expression correlated with inhibition of mTOR signaling, and an increase in autophagy markers. siRNA ablation of DDiT4L revealed that inhibition of mTOR signaling by DDiT4L was necessary for glucose deprivation induced autophagy, as determined by imaging of GFP-LC3 autophagosomes (n = 3 in duplicate, p<0.01), and immunoblotting of autophagy markers. Conversely, adenoviral-driven overexpression of DDiT4L inhibited mTOR signaling and significantly increased basal autophagy (n = 3 in duplicate, p<0.05). In TAC mice, the increase in DDiT4L protein expression correlated to inhibition of mTOR signaling, increases in autophagy markers (p<0.01), and preceded the transition to LV dilation and HF. Conclusion: Our data suggests that DDiT4L expression is altered in diverse models of pathological hypertrophy and precedes the development of LV dilatation and overt heart failure. DDiT4L inhibition of mTOR and modulation of autophagy may play a role in the progression to heart failure. DDiT4L may represent a novel therapeutic target to prevent this transition.

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Role of Oxidative Stress in Heart Failure: Insights from Gene Transfer Studies

Biomedicines ◽

10.3390/biomedicines9111645 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1645

Author(s):

Bart De Geest ◽

Mudit Mishra

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Gene Therapy ◽

Steady State ◽

Gene Transfer ◽

Oxidative Modification ◽

Heme Oxygenase 1 ◽

Therapy Studies ◽

Pathological Remodeling

Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure.

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Relationship between electrical myocardial instability and postinfarction remodeling in patients with ST-segment elevation myocardial infarction

Kardiologiia ◽

10.18087/cardio.2021.10.n1626 ◽

2021 ◽

Vol 61 (10) ◽

pp. 14-25

Author(s):

V. E. Oleynikov ◽

Yu. A. Barmenkova ◽

E. V. Dushina ◽

A. V. Golubeva

Keyword(s):

Quality Of Life ◽

Myocardial Infarction ◽

Left Ventricular ◽

Myocardial Remodeling ◽

Phase Duration ◽

St Segment Elevation ◽

Segment Elevation Myocardial Infarction ◽

St Segment ◽

Pathological Remodeling

Aim To study the clinical value of markers for myocardial electrical instability in combination with echocardiographic parameters for predicting the risk of cardiovascular complications (CVC) in the postinfarction period.Material and methods This study included 118 patients with ST segment elevation myocardial infarction (STEMI) and hemodynamically significant stenosis of one coronary artery. A percutaneous coronary intervention (PCI) with stenting of the infarct-related artery was performed for all patients. On day 7-9 and at 24 and 48 weeks after the treatment, ECG Holter monitoring was performed, which included analyses of ventricular late potentials, dispersion of QT interval duration, heart rate turbulence (HRT) and variability (HRV), and heart chronotropic load (HCL). At baseline and during postinfarction week 12, all patients underwent echocardiography with calculation of indexes of end-diastolic volume (iEDV) and end-systolic volume (iESV) to verify the signs of left ventricular (LV) myocardial remodeling. The criteria for LV pathological remodeling included increases in iEDV >20 % and/or iESV >15 % at 12 weeks after STEMI. The group without remodeling, R(-), consisted of 79 (67 %) patients and the group with signs of LV pathological remodeling, R(+), consisted of 39 (33 %) patients. Quality of life and achieved endpoints were evaluated during 144 weeks.Results By week 48 in group R(-), the stabilization of electrical processes in the myocardium was more pronounced as indicated by a decrease in HFLA by 12 % (р=0.004) and by a fourfold increase in RMS (р=0.047). Only in this group, the baroreflex sensitivity restored; pathological ТРС decreased from 20 to 5% (p=0.002) by the end of the active treatment. Stabilization of the repolarization phase duration in various parts of the myocardium was more active in patients without pathological remodeling as shown by decreases in disp QTa (р=0.009), disp QTe (р=0.03), sd QTa (р=0.006), and sd QTe (р=0.009). This was not observed in the group R(+). The recovery of vagosympathetic balance due to leveling the sympathetic component also was more effective in the group R(-), which was reflected in increased spectral and temporal HRV indexes (р<0.05). Both groups showed reduced HCL values at 24 weeks (р=0.047 and р=0.006); however, the HCL regression remained also at 48 weeks only in the group R(-) (р=0.006). Group R(-) patients reported higher quality of life (р=0.03) than group R(+) patients. Endpoints were achieved more frequently in the group R(+): 87.1 % vs. 27.8 % (odds ratio, 11.8; 95 % confidence interval, 4.6–30.8; р=0.00001).Conclusion Pathological myocardial remodeling in early postinfarction period is associated with electrophysiological instability of the myocardium, which results in the development of CVC and low quality of life in patients with STEMI.

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Abstract 238: Loss of AKAP150 Promotes Pathological Remodeling and Heart Failure Propensity by Disrupting Calcium Homeostasis and Contractile Reserve

Circulation Research ◽

10.1161/res.119.suppl_1.238 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Lei Li ◽

Jing Li ◽

Benjamin Drum ◽

Yi Chen ◽

Haifeng Yin ◽

...

Keyword(s):

Heart Failure ◽

Critical Role ◽

Pressure Overload ◽

Contractile Reserve ◽

Mouse Heart ◽

Adrenergic Stimulation ◽

Anchoring Protein ◽

Key Aspects ◽

Myocyte Contractility ◽

Pathological Remodeling

Impaired Ca 2+ cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca 2+ cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signaling complexes in the pathogenesis of heart failure is largely unknown. Here we investigate how AKAP150 signaling complexes impact Ca 2+ cycling, myocyte contractility, and heart failure susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predisposed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodeling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not appear to affect chronic activation of calcineurin-NFAT signaling in cardiomyocytes or pressure overload- or agonist- induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca 2+ regulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca 2+ cycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload. These findings define a critical role for AKAP150 in maintaining Ca 2+ homeostasis and myocardial ionotropy following pathological stress, suggesting the AKAP150 signaling pathway may serve as a novel therapeutic target for heart failure.

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Abstract 425: A Pro-reductive Redox State Protects the Myocardium From Isoproterenol-Induced Pathological Remodeling in Nrf2 Transgenic Mouse

Circulation Research ◽

10.1161/res.123.suppl_1.425 ◽

2018 ◽

Vol 123 (Suppl_1) ◽

Author(s):

Gobinath Shanmugam ◽

Anil Kumar Challa ◽

Silvio H Litovsky ◽

Jolyn Fernandes ◽

Dean P Jones ◽

...

Keyword(s):

Transgenic Mouse ◽

Redox State ◽

Pathological Remodeling

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