Abstract 71: STAT3 Affects Myofibrillar Structure and Its Loss May Contribute to Heart Failure in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Fouad Zouein ◽  
Carlos Zgheib ◽  
John Fuseler ◽  
John E Hall ◽  
Mazen Kurdi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Transcriptional Activity ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Systolic Dysfunction ◽  
Wild Type ◽  
Patients With Heart Failure ◽  
Protective Proteins ◽  
Fractional Shortening

How hypertension causes heart failure is not known. Since patients with heart failure have reduced cardiac STAT3 and STAT3 KO mice develop heart failure with age, we tested the hypothesis that reduced STAT3 transcriptional activity contributes at an early stage to remodeling that precedes heart failure in hypertension using SA mice with a STAT3 S727A mutation. SA and wild type (WT) mice received angiotensin (A) II (1000 ng/kg/min) or saline (S) for 17 days. Hearts of WT and SA mice had similar levels of STAT3-induced protective proteins Bcl-xL and SOD2, and unlike STAT3 KO mice, cardiac miR-199a levels were not increased in SA mice. AII increased systolic blood pressure measured by telemetry in SA (124 ± 1 to 167 ± 3) and WT (122 ± 3 to 162 ± 3) mice to the same extent. AII increased cardiac levels of cytokines (pg/μg protein) associated with heart failure in both WT and SA mice, but significantly less so (P<0.05) in SA mice; IL-6, 13.6 ± 1.4 vs. 9.1 ± 0.6; TGFβ, 56 ± 4 vs. 38 ± 3 and MCP1 35 ± 2 vs. 22 ± 2. Compared to WT mice, hearts of SA mice showed signs of developing systolic dysfunction with AII as seen by a significant (P<0.05) reduction in ejection fraction (63.7 ± 7.1 to 51.7 ± 6.9) and fractional shortening (34.3 ± 4.9 to 26.4 ± 4.3). AII caused fibrosis in the left ventricle of both WT and SA mice characterized by cardiac myocyte loss and increased % collagen: WT+S, 5.59 ± 0.34; WT+AII, 15.70 ± 1.87; SA+S, 6.70 ± 0.40; SA+AII, 16.50 ± 1.91. In WT+AII mice there was a nonsignificant trend towards a loss of myofibrillar content of cardiac myocytes, but an increase in the mass of the myofibrils (IOD/myofibrillar area). In contrast, cardiac myocytes of SA+AII mice had a significant (P<0.001) % loss in myofibrils (5.71 ± 0.28) compared to SA+S (0.75 ± 0.07), WT+S (0.80 ± 0.06) and WT+AII (1.54 ± 0.10) mice. In addition, the mass of the myofibrils in SA+AII mice (6.01 ± 0.07) was significantly less (P<0.001) than those of SA+S mice (6.46 ± 0.04), although greater than WT+S (4.85 ± 0.06) or WT+AII (5.27 ± 0.08) mice. Our findings reveal that STAT3 transcriptional activity is important for proper morphology of the myofibrils of cardiac myocytes. Loss of STAT3 activity may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

scholarly journals Interleukin-18 mediates interleukin-1-induced cardiac dysfunction

2014 ◽  
Vol 306 (7) ◽  
pp. H1025-H1031 ◽  
Author(s):  
Stefano Toldo ◽  
Eleonora Mezzaroma ◽  
Laura O'Brien ◽  
Carlo Marchetti ◽  
Ignacio M. Seropian ◽  
...  
Keyword(s):  
Systolic Dysfunction ◽  
Interleukin 1 ◽  
Left Ventricular ◽  
Wild Type ◽  
Blocking Antibody ◽  
Experimental Mouse Model ◽  
Patients With Heart Failure ◽  
Experimental Mouse ◽  
Genetic Deletion ◽  
Fractional Shortening

Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1β in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30–50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1β induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1β failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1β induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1β. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.

Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

2007 ◽  
Vol 29 (3) ◽  
pp. 246-252 ◽  
Author(s):  
Natale P. L. Rolim ◽  
Alessandra Medeiros ◽  
Kaleizu T. Rosa ◽  
Katt C. Mattos ◽  
Maria C. Irigoyen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Cardiac Myocyte ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Exercise Intolerance ◽  
Computer Assisted ◽  
Wild Type ◽  
Beneficial Effects ◽  
Ventricular Fibrosis

The molecular basis of the beneficial effects associated with exercise training (ET) on overall ventricular function (VF) in heart failure (HF) remains unclear. We investigated potential Ca2+ handling abnormalities and whether ET would improve VF of mice lacking α2A- and α2C-adrenoceptors (α2A/α2CARKO) that have sympathetic hyperactivity-induced HF. A cohort of male wild-type (WT) and congenic α2A/α2CARKO mice in a C57BL/J genetic background (5–7 mo of age) was randomly assigned into untrained and trained groups. VF was assessed by two-dimensional guided M-mode echocardiography. Cardiac myocyte width and ventricular fibrosis were evaluated with a computer-assisted morphometric system. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2), phospholamban (PLN), phospho-Ser16-PLN, phospho-Thr17-PLN, phosphatase 1 (PP1), and Na+-Ca2+ exchanger (NCX) were analyzed by Western blotting. ET consisted of 8-wk running sessions of 60 min, 5 days/wk. α2A/α2CARKO mice displayed exercise intolerance, systolic dysfunction, increased cardiac myocyte width, and ventricular fibrosis paralleled by decreased SERCA2 and increased NCX expression levels. ET in α2A/α2CARKO mice improved exercise tolerance and systolic function. ET slightly reduced cardiac myocyte width, but unchanged ventricular fibrosis in α2A/α2CARKO mice. ET significantly increased the expression of SERCA2 (20%) and phospho-Ser16-PLN (63%), phospho-Thr17-PLN (211%) in α2A/α2CARKO mice. Furthermore, ET restored NCX and PP1 expression in α2A/α2CARKO to untrained WT mice levels. Thus, we provide evidence that Ca2+ handling is impaired in this HF model and that overall VF improved upon ET, which was associated to changes in the net balance of cardiac Ca2+ handling proteins.

scholarly journals Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (2) ◽  
pp. 161-174 ◽  
Author(s):  
Sarah Karam ◽  
Jean Piero Margaria ◽  
Aurélia Bourcier ◽  
Delphine Mika ◽  
Audrey Varin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mouse ◽  
Adrenergic Receptor ◽  
Systolic Dysfunction ◽  
Fold Increase ◽  
Aortic Constriction ◽  
Adeno Associated Virus ◽  
Transgenic Mouse Line ◽  
Virus Serotype ◽  
Fractional Shortening

Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

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