scholarly journals Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 143
Author(s):  
Synne S. Hansen ◽  
Tina M. Pedersen ◽  
Julie Marin ◽  
Neoma T. Boardman ◽  
Ajay M. Shah ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Mechanical Efficiency ◽  
Substrate Utilization ◽  
Low Doses ◽  
Myocardial Substrate

The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

Abstract 16267: NADPH Oxidase Nox4 Up-regulation Contributes to the Worsening of Pressure Overload-induced Cardiac Dysfunction in Angiopoeitin-like 2 Knockdown Mice

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Cécile Martel ◽  
Adeline Raignault ◽  
Carol Yu ◽  
Marc-Antoine Gillis ◽  
Maya Mamarbachi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Diastolic Pressure ◽  
Vascular Inflammation ◽  
Pressure Overload ◽  
Mrna And Protein Expression ◽  
Contraction And Relaxation

Background: Angiopoietin-like 2 (angptl2) is a circulating protein promoting vascular inflammation and endothelial dysfunction in mice, but little is known on its impact on cardiac function. Our previous results suggest that knocking down angptl2 in mice (KD) worsens pressure overload-induced cardiac dysfunction while preserving cerebral artery structure and endothelial function. As NADPH oxidase NOX4 is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes but also a vasodilatory factor, we hypothesized that increased expression of NOX4 contributes to the aggravated cardiac dysfunction observed in KD mice. Methods/Results: Cardiac function was measured in vivo by Millar catheter in KD mice versus their wild-type (WT) littermates in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). Concomitantly to a worsened cardiac remodeling and an aggravated cardiac dysfunction compared to WT-TAC mice, only KD-TAC mice displayed an increase in cardiac mRNA and protein expression of NOX4 (p<0.05 vs. WT, n=8). To specifically decrease cardiac NOX4 expression, we performed, two weeks after TAC surgery, a single i.v. injection of cardiac specific associated adenovirus AAV9 expressing a NOX4-targeted shRNA or a scrambled shRNA. In KD-TAC mice, the AAV9-shNOX4 limited cardiac hypertrophy as evidenced by a smaller heart/tibia ratio (Table, * p<0.05). Moreover, cardiac function in KD-TAC-AAV9-shNOX4 mice was partly prevented by maintaining contraction and relaxation maximal velocities and by limiting the abnormal rise of minimal pressure and end diastolic pressure caused by TAC (Table, * p<0.05). Conclusion: Angptl2 knockdown worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload: cardiac up-regulation of NOX4 could contribute to these deleterious effects in angptl2 KD mice.

Abstract 47: Loss of the Cardio Protection Inferred by S-nitrosylation of GRK2 At Cysteine 340 Leads to Decreased Cardiac Performance and a Hypertensive Phenotype With Aging

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
Walter Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Cardio Protection ◽  
G Protein Coupled ◽  
Global Population

In the next 35 years, the global population of individuals above 60 years of age will double to approximately 2 billion. In the aged population, cardiovascular diseases are known to occur at a higher prevalence ultimately leading to increased mortality. G protein-coupled receptors (GPCRs) have been identified as vital regulators of cardiac function. GPCR kinases (GRKs) are important in cardiac GPCR regulation through desensitization of these receptors. GRK2 is highly expressed in the heart, and has been widely characterized due to its upregulation in heart failure. Studies from our lab have shown that elevated GRK2 levels in ischemia-reperfusion (I/R) injury result in a pro-death phenotype. Interestingly, cardio-protection can be inferred via S-nitrosylation of GRK2 at cysteine 340. Further, we have generated a knock-in GRK2 340S mouse, in which cysteine 340 was mutated to block dynamic GRK2 S-nitrosylation. GRK2 340S mice are more susceptible to I/R injury. Given that GRK2 340S mice are more susceptible to oxidative stress, and there is a nitroso-redox imbalance in senescence, it is possible that these mice are more likely to exhibit decreased cardiac performance as they age. Therefore, we hypothesize that with age GRK2 340S knockin mice will develop an overall worsened cardiac phenotype compared to control wild-type (WT) mice. To test this hypothesis, 340S and WT mice were aged for a year, and cardiac function was evaluated via echocardiography. Aged 340S mice exhibited significantly decreased ejection fraction and fraction shortening relative to aged WT controls. Prior to tissue harvesting, in-vivo hemodynamics was conducted via Millar catheterization. At baseline, aged 340S mice exhibited increased systolic blood pressure compared to aged WT mice. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured to evaluate cardiac hypertrophy. Aged 340S mice exhibited significantly increased HW/BW and HW/TL ratios, indicative of cardiac hypertrophy, relative to aged WT controls. Taken together, these data suggest that with age, loss of the cardio protection inferred by S-nitrosylation of GRK2 at leads to decreased cardiac performance, and an overall worsened cardiac phenotype.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

scholarly journals Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin-Tong Wang ◽  
Zhen Peng ◽  
Ying-Ying An ◽  
Ting Shang ◽  
Guangxu Xiao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Tissue ◽  
Myocardial Dysfunction ◽  
Cecal Ligation ◽  
Hydroxysafflor Yellow A ◽  
Sepsis Management ◽  
Xuebijing Injection

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

scholarly journals CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

2019 ◽  
Vol 20 (9) ◽  
pp. 2267 ◽  
Author(s):  
Thomas J. LaRocca ◽  
Perry Altman ◽  
Andrew A. Jarrah ◽  
Ron Gordon ◽  
Edward Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Subsequent Increase ◽  
Transition Electron Microscopy ◽  
Cardiac Phenotype

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to β-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates β-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.

scholarly journals Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade

2015 ◽  
Vol 112 (16) ◽  
pp. 5141-5146 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Ruriko Grant ◽  
John R. Hagaman ◽  
Sylvia Hiller ◽  
Feng Li ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Young Adult ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Contractile Function ◽  
Wild Type ◽  
Endothelin 1 ◽  
Mmp9 Expression ◽  
Four Levels ◽  
Metalloproteinase 9

We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.

scholarly journals Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

2017 ◽  
Vol 114 (45) ◽  
pp. 12033-12038 ◽  
Author(s):  
Iacopo Gesmundo ◽  
Michele Miragoli ◽  
Pierluigi Carullo ◽  
Letizia Trovato ◽  
Veronica Larcher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Therapeutic Potential ◽  
Growth Hormone Releasing Hormone ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

scholarly journals Extracellular SPARC improves cardiomyocyte contraction during health and disease

2018 ◽  
Author(s):  
Sophie Deckx ◽  
Daniel M. Johnson ◽  
Marieke Rienks ◽  
Paolo Carai ◽  
Elza van Deel ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Matrix Protein ◽  
Contractile Function ◽  
Ex Vivo ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Coxsackie Virus ◽  
Extracellular Matrix Protein

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and in lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly improves cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.

Necrostatin-1 reduces cardiac and mitochondrial dysfunction in prediabetic rats

2021 ◽  
Author(s):  
Nattayaporn Apaijai ◽  
Kewarin Jinawong ◽  
Kodchanan Singhanat ◽  
Thidarat Jaiwongkam ◽  
Sasiwan Kerdphoo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Mitochondrial Dysfunction ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Metabolic Parameters ◽  
Vehicle Group ◽  
Mitochondrial Dynamic ◽  
Autonomic Imbalance

High fat diet (HFD) consumption induces prediabetes and left ventricular dysfunction through many pathways including the cell death pathway, necroptosis. Although benefits of necroptosis inhibitor (necrostatin-1 or Nec-1) in the brain of prediabetic rats have been shown, the effects of Nec-1 on cardiac autonomic function, blood pressure, and cardiac function, and the mechanisms involved have not been investigated. Male Wistar rats were fed with either a normal diet (n=8) or HFD (n=24) for 12 weeks to induce prediabetes. Prediabetic rats were randomly assigned into 3 interventional groups (n=8/group): 1) vehicle, 2) Nec-1 (1.65 mg/kg, sc injection), and 3) metformin (300 mg/kg, oral gavage feeding). Treatments lasted for 8 weeks. Normal saline was given to the vehicle group and a non-interventional group. Metabolic parameters, cardiac function and biochemical parameters were assessed. Prediabetic rats exhibited peripheral metabolic impairment as indicated by increased body weight, hyperinsulinemia with euglycemia, and dyslipidemia. Prediabetic rats also exhibited cardiac autonomic imbalance, high blood pressure, cardiac dysfunction, cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and increased necroptosis and apoptosis. Treatment with Nec-1 did not affect peripheral metabolic parameters, however it effectively reduced cardiac autonomic imbalance, blood pressure, and cardiac dysfunction via reduced cardiac inflammation, necroptosis, mitochondrial dysfunction, and increased mitochondrial fusion. Treatment with metformin reduced peripheral metabolic impairment and cardiac dysfunction via decreased cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. In summary, Nec-1 directly suppressed necroptosis, cardiac mitochondrial dysfunction, and increased mitochondrial fusion independent to peripheral metabolic function, leading to an improvement in cardiac function in prediabetic rats.

Sign in / Sign up

Export Citation Format

Share Document