Abstract 86: Cardiomyocyte-Specific Ablation of Nuclear Respiratory Factor 1 in the Mouse Leads to Dysregulation of Mitochondrial Biogenesis, Apoptosis, and Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jeffrey E Keenan ◽  
Hagir Sulliman ◽  
Allison Ulrich ◽  
Lan Mao ◽  
Claude A Piantadosi
Keyword(s):  
Heart Failure ◽  
Mitochondrial Biogenesis ◽  
Structural Integrity ◽  
Left Ventricular ◽  
Nuclear Condensation ◽  
Nuclear Respiratory Factor ◽  
Protein Levels ◽  
Mitochondrial Homeostasis ◽  
Nuclear Respiratory Factor 1

The DNA-binding transcription factor Nuclear Respiratory Factor 1 (NRF1) regulates mitochondrial homeostasis. Its constitutive ablation in the mouse is embryonically lethal (~E3.5). This has limited our understanding of NRF1 functionality in the heart, where mitochondrial dysfunction is often a major pathogenic factor. Therefore, we generated conditional cardiomyocyte-specific NRF1 knockout mice (MYH6-mer-Cre-mer-NRF1fl/fl or NRFfl/fl) to elucidate the role of cardiac NRF1. Two weeks after NRF1 silencing, echocardiography of NRF1fl/fl hearts revealed significant reductions in left ventricular fractional shortening (Figure A). Histology demonstrated degradation of cellular structural integrity and nuclear condensation (Figure B), with a high number of TUNEL positive nuclei compared to littermate controls (MYH6-mer-Cre-mer-NRF-1wt), indicative of apoptosis (37.8% vs. 1.1%, p < 0.001). The mRNA and protein levels of key mediators of mitochondrial biogenesis were evaluated by real-time RT-PCR and immunoblotting (Figure C & D). Compared to littermate controls, there was down-regulation of the mitochondrial encoded NADH dehydrogenase 1, implying a reduction of functional mitochondrial mass. Key biogenesis regulators PGC1-α (protein only), Nfe2l2, and NRF2 were also reduced. In total, these data support that dysregulation of mitochondrial biogenesis after loss of NRF1 results in cardiomyocyte apoptosis and reduced left ventricular function. These findings and further delineation of the mechanisms involved should lay the foundation for the exploitation of NRF1 as a therapeutic target in heart failure.

The effect of oestrogen withdrawal on cardiac Ca2+ regulation and the influence of GPER1

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.J Francis ◽  
J.M Firth ◽  
N Islam ◽  
J Gorelik ◽  
K.T MacLeod
Keyword(s):  
Heart Failure ◽  
Structural Integrity ◽  
Left Ventricular ◽  
Funding Source ◽  
Hormonal Changes ◽  
Ion Conductance ◽  
Developing Heart ◽  
Rapid Stimulation ◽  
Post Menopausal

Abstract Background Post-menopausal women have an enhanced risk of developing heart failure, attributed to declining oestrogen levels during menopause. However, the signalling mechanisms remain undetermined. Purpose We aim to determine the role of G-protein coupled oestrogenic receptor 1 (GPER1) in intracellular Ca2+ regulation and the consequences of hormonal changes that may exacerbate the pathophysiology of heart failure. Methods Ovariectomy (OVx) (mimics menopausal hormone changes) or sham surgeries were conducted on female guinea pigs. Left ventricular cardiomyocytes were isolated 150-days post-operatively for experimental use. Cellular t-tubule network and structural integrity was measured using fluorescent di-8-ANEPPs staining and scanning ion conductance microscopy. GPER1 expression and localisation was measured by Western blot and immunostaining. The role of GPER1 activation was measured using selective agonist G-1 in electrophysiological and Ca2+-sensitive dye fluorescence experiments. Results Following oestrogen withdrawal, the t-tubule network density decreased by 13% and z-groove index reduced by 15%. GPER1 predominantly localised to the peri-nuclear endoplasmic reticulum and its expression increased by 32% in OVx. Action potential duration (APD) prolonged in OVx and following GPER1 activation, APD90 shortened by 11% and 25% in sham and OVx respectively. OVx cells had larger peak inward Ca2+ current (ICaL) (by 22%) and sarcoplasmic reticulum (SR) Ca2+ content (by 13%), compared with sham. While GPER1 activation had little effect on peak ICaL or SR content, it reduced Ca2+ transient amplitude (by 20%), SR fractional release (by 11%) in OVx cells. The frequency of occurrence of spontaneous Ca2+ waves evoked by periods of rapid stimulation reduced by 40% and wave-free survival time prolonged in OVx cells following GPER1 activation. Conclusions In the hearts of an animal species whose electrophysiology and intracellular Ca2+ regulation is akin to humans, we show that following oestrogen deficiency, the t-tubule network is down-regulated and becomes disorganised, GPER1 expression is increased and its activation induces negative inotropic responses in cardiomyocytes. This may limit the adverse changes to Ca2+ signalling reported in OVx that could be pro-arrhythmic and exacerbate the progression to heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

scholarly journals Dysfunction of the β2-spectrin-based pathway in human heart failure

2016 ◽  
Vol 310 (11) ◽  
pp. H1583-H1591 ◽  
Author(s):  
Sakima A. Smith ◽  
Langston D. Hughes ◽  
Crystal F. Kline ◽  
Amber N. Kempton ◽  
Lisa E. Dorn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Left Ventricle ◽  
Small Animal ◽  
Left Ventricular ◽  
Effector Proteins ◽  
Human Heart Failure ◽  
Protein Levels ◽  
Ankyrin B

β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca2+- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca2+- and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca2+- and calpain-dependent proteolysis.

Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

1999 ◽  
Vol 5 (3) ◽  
pp. 79
Author(s):  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui ◽  
Tomomi Ide ◽  
Hideo Ustumi ◽  
Nobuhiro Suematsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

Abstract 13320: Direct Cardiac Actions of Empagliflozin Improve Mitochondrial Oxidative Phosphorylation and Attenuate Pressure-overload Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xuan Li ◽  
Jussara M do Carmo ◽  
Zhen Wang ◽  
Alexandre A da Sivla ◽  
Alan J Mouton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Molecular Docking ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporters ◽  
Left Ventricular ◽  
Mitochondrial Morphology ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Docking Analysis ◽  
Molecular Docking Analysis

Introduction: The underlying mechanisms by which empagliflozin (EMPA) and other sodium glucose co-transporter 2 (SGLT2) inhibitors attenuate heart failure (HF) are still poorly understood. However, this protection does not appear to be fully explained by their antihyperglycemic or diuretic effects. Hypothesis: EMPA attenuates HF by direct effects on the heart to improve its metabolism and function. Methods: C57BL/6J mice (4-6 months) were subjected to transverse aortic constriction (TAC) or sham surgeries. Two weeks after TAC, EMPA (10 mg/kg/day) or vehicle was administered daily for 4 additional weeks. Cardiac function was assessed by echocardiography and cardiac substrate metabolism measured in isolated perfused hearts. Transmission electron microscopy was used to evaluate mitochondrial morphology and molecular docking analysis to predict potential cardiac targets of EMPA. Results: EMPA increased survival and attenuated adverse left ventricle remodeling and cardiac fibrosis after TAC. EMPA also attenuated left ventricular systolic dysfunction (ejection fraction 51.6 vs. 40.2% p<0.05; fraction shortening 28.8 vs 18.4% p<0.05). EMPA rescued impaired glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. Molecular docking analysis and isolated perfused heart experiments indicated that EMPA can directly bind glucose transporters in the heart to reduce glycolysis, and enhance AMP-activated protein kinase. EMPA treatment enhanced mitochondrial biogenesis, restored mitochondria cristae integrity, increased expression of endogenous antioxidants, and reduced cellular apoptosis caused by leakage of cytochrome C from mitochondria into the cytosol. These beneficial cardiac effects of EMPA occurred despite no alterations in fasting blood glucose, body weight, or daily urine volume. Conclusions. Our study demonstrated that EMPA may directly bind glucose transporters and reduce excessive glycolysis in failing hearts. EMPA enhanced mitochondrial biogenesis, improved mitochondrial oxidative phosphorylation, and reduced mitochondria-mediated apoptosis, thereby attenuating cardiac dysfunction and progression of HF.

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Heng-Jie Cheng ◽  
Tiankai Li ◽  
Che Ping Cheng
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Adrenergic Receptors ◽  
Left Ventricular ◽  
Male Rats ◽  
Protein Levels ◽  
Myocyte Function ◽  
Oxide Synthase ◽  
Β Adrenergic Receptors

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF. Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF , 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL , 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C). Results: Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (E ES , HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca 2+ ] iT (0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10 -8 M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β 1 -AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB Ser16 /PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β 3 -AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca 2+ ] iT , and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β 1 - and β 3 -AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77). Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β 1 -AR and reverse contrast changes between iNOS and β 3 -AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve.

scholarly journals Is there a link between glucose levels and heart failure? An update

2010 ◽  
Vol 54 (5) ◽  
pp. 488-497 ◽  
Author(s):  
Arnaldo Schainberg ◽  
Antônio Ribeiro-Oliveira Jr. ◽  
José Marcio Ribeiro
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Epidemiological Studies ◽  
Left Ventricular ◽  
Glucose Levels ◽  
Factors Analysis ◽  
History Of ◽  
Cv Disease ◽  
The Relationship

It has been well documented that there is an increased prevalence of standard cardiovascular (CV) risk factors in association with diabetes and with diabetes-related abnormalities. Hyperglycemia, in particular, also plays an important role. Heart failure (HF) has become a frequent manifestation of cardiovascular disease (CVD) among individuals with diabetes mellitus. Epidemiological studies suggest that the effect of hyperglycemia on HF risk is independent of other known risk factors. Analysis of datasets from populations including individuals with dysglycemia suggests the pathogenic role of hyperglycemia on left ventricular function and on the natural history of HF. Despite substantial epidemiological evidence of the relationship between diabetes and HF, data from available interventional trials assessing the effect of a glucose-lowering strategy on CV outcomes are limited. To provide some insight into these issues, we describe in this review the recent important data to understand the natural course of CV disease in diabetic individuals and the role of hyperglycemia at different times in the progression of HF.

scholarly journals The role of systemic inflammation in heart failure

2021 ◽  
Vol 102 (4) ◽  
pp. 510-517
Author(s):  
E V Khazova ◽  
O V Bulashova
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Systemic Inflammation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
C Reactive Protein ◽  
Ventricular Ejection Fraction ◽  
Reactive Protein ◽  
Highly Sensitive

The discussion continues about the role of systemic inflammation in the pathogenesis of cardiovascular diseases of ischemic etiology. This article reviews the information on the role of C-reactive protein in patients with atherosclerosis and heart failure in risk stratification for adverse cardiovascular events, including assessment of factors affecting the basal level of highly sensitive C-reactive protein. Research data (MRFIT, MONICA) have demonstrated a relationship between an increased level of C-reactive protein and the development of coronary heart disease. An increase in the serum level of highly sensitive C-reactive protein is observed in arterial hypertension, dyslipidemia, type 2 diabetes mellitus and insulin resistance, which indicates the involvement of systemic inflammation in these disorders. Currently, the assessment of highly sensitive C-reactive protein is used to determine the risk of developing myocardial infarction and stroke. It has been proven that heart failure patients have a high level of highly sensitive C-reactive protein compared with patients without heart failure. The level of C-reactive protein is referred to as modifiable risk factors for cardiovascular diseases of ischemic origin, since lifestyle changes or taking drugs such as statins, non-steroidal anti-inflammatory drugs, glucocorticoids, etc. reduce the level of highly sensitive C-reactive protein. In patients with heart failure with different left ventricular ejection fraction values, it was found that the regression of the inflammatory response is accompanied by an improvement in prognosis, which confirms the hypothesis of inflammation as a response to stress, which has negative consequences for the cardiovascular system.

scholarly journals Role of interleukin-18 and plasma B-type natriuretic peptide in predicting requirement of kidney replacement therapy and/or mortality in individuals with acute heart disorders

2019 ◽  
Vol 8 (4) ◽  
pp. 292-300
Author(s):  
Aida Hamzić-Mehmedbašić ◽  
Damir Rebić ◽  
Amina Valjevac ◽  
Hajrunisa Čubro ◽  
Azra Durak Nalbantić ◽  
...  
Keyword(s):  
Heart Failure ◽  
Replacement Therapy ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Apache Ii Score ◽  
Interleukin 18 ◽  
Cutoff Value ◽  
Coronary Syndrome ◽  
Heart Disorders

Introduction: Although many predictive tools have already been developed, efforts are still proceeding to identify a reliable biomarker to predict the prognosis of the patients with acute heart disorders. Objectives: The aim was to evaluate the role of renal injury biomarkers (serum cystatin C, serum and urine interleukin-18, IL-18) and heart failure biomarkers (plasma B-type natriuretic peptide, BNP) in the prediction of the postdischarge requirement of renal replacement therapy (RRT) and/or 6-month mortality in patients with acute heart disorders. Patients and Methods: In patients diagnosed with acute heart disorders (acute heart failure [AHF] and/or acute coronary syndrome [ACS]) and admitted to the intensive care units, baseline clinical parameters, renal and cardiac biomarkers were determined. Patients were followed up for 6 months. The composite outcome was the postdischarge requirement of RRT and/or 6-month mortality. Results: Of 120 patients, 5.8% continued RRT after discharge. The 6-month mortality was 20%. Cox logistic regression analysis showed that urine IL-18 (P=0.021), plasma BNP (P=0.046), Acute Physiology and Chronic Health Evaluation (APACHE) II score (P=0.002), and left ventricular diastolic dysfunction (P=0.045) were independent predictors of the postdischarge requirement of RRT and/or 6-month mortality. For predicting RRT and/or 6-month mortality, using urine IL-18 cutoff value of 29.1 pg/mL showed 66.7% sensitivity and 67.7% specificity (area under the curve, AUC 0.70, P=0.003), while using plasma BNP cutoff value of 881.6 pg/mL showed 66.7% sensitivity and 70.8% specificity (AUC 0.76, P<0.001). Conclusion: Urine IL-18 and plasma BNP are independently predictive for the postdischarge requirement of RRT and/or 6-month mortality in patients with acute heart disorders.

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