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.

Abstract 338: Cardiac Overexpression of Creatine Kinase Improves Cardiomycytes Function in Heart Failure and During Increased Redox Stress

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Carlo G Tocchetti ◽  
Michelle Leppo ◽  
Djahida Bedja ◽  
Yibin Wang ◽  
Robert G Weiss ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Dysfunction ◽  
Similar Response ◽  
Wild Type ◽  
Aortic Constriction ◽  
Redox Stress ◽  
Adult Cardiomyocytes ◽  
Metabolic Role ◽  
Myocyte Function ◽  
Fractional Shortening

Aims: Several studies suggest that abnormal energy metabolism contributes to heart failure or that the failing heart is energy starved. Here we aim at testing whether an increase in intracellular CK improves myocellular contractility in experimental myocardial dysfunction and protects from increased oxidative conditions. Methods-Results: We tested the response to the β-agonist isoproterenol (2.5 nM, ISO) in field-stimulated (.5 Hz, RT) adult cardiomyocytes isolated from wild-type (WT) mice and mice overexpressing cardiac myofibrillar or mitochondrial CK (CK-M or CK-mito) from sham and failing (8 wk transverse aortic constriction (TAC)) hearts, to dissect whether overexpressing CK alters myocyte function at baseline and during increased energetic demand. There were no differences in sarcomere fractional shortening (FS) or Ca2+ transients at baseline and with ISO among sham WT, CK-M or CK-mito myocytes. However, ISO effects were significantly reduced in WT TAC myocytes, consistent with prior reports. Conversely, in CK-M or CK-mito TAC myocytes, ISO-induced inotropy was fully preserved. Interestingly, incubation with the AMPK-stimulator AICAR (1mM for at least 90’) did not have any effect on WT TAC, but increased FS in TAC CK-M (+82%) and CK-mito (+42%) myocytes significantly, supporting the important metabolic role played by enhancing CK in failing hearts. To test whether overexpressing CK-M or CK-mito confer protection against acute oxidative stress, sham myocytes were exposed to H2O2 (50μM, 10’) and the interval (seconds) between the beginning of H2O2 superfusion and the appearance of irreversible arrhythmias was measured. WT and CK-M myocytes had a similar response (416±91s vs 411±68s), whereas in CK-mito this interval was significantly prolonged (600±64s). Similarly, upon acute infusion of the anticancer TKI sunitinib (2μM), whose cardiotoxic properties have been linked also to an increase in ROS, irreversible arrhythmias appeared after 657±43s in CK-mito (p<.5 vs 561±66 for WT and 467±88 for CK-M). Conclusions: Overexpressing CK-M and CK-mito under failing-TAC conditions improves myocyte function likely through better preserved Ca2+ handling, whereas only the up-regulation of CK-mito is more effective in buffering ROS effects.

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 Morphologically proved ANCA positive Loeffler’s pancarditis: medical and surgical treatment

2019 ◽  
Vol 91 (4) ◽  
pp. 99-106 ◽  
Author(s):  
O V Blagova ◽  
I N Aliyeva ◽  
A V Nedostup ◽  
E A Kogan ◽  
R N Komarov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Thrombus Formation ◽  
Systolic Dysfunction ◽  
Fold Increase ◽  
Left Ventricular ◽  
Oval Window ◽  
Cationic Protein ◽  
The Right ◽  
Immunohistochemical Studies ◽  
Active Inflammation

Loeffler's endocarditis remains is a very rare disease, develops due to eosinophilic inflammation predominantly of the endocardium with an outcome in fibrosis and massive thrombus formation and. He is generally characterized by an unfavorable prognosis. Clinical case of a 42-year-old patient with Loeffler endocarditis is presented. The development of the disease was preceded by a polyvalent allergy, mild dry eye syndrome and pansinusitis with a single eosinophilia of blood up to 16%. The reason for the hospitalization was the appearance of biventricular heart failure. During the previous year, the level of blood eosinophils remained normal, a threefold increase in the level of eosinophilic cationic protein was observed once. A 20-fold increase in the pANCA level, a 2.5-fold increase in the level of antibodies to DNA, an antibody to the nuclei of cardiomyocytes 1:160 were detected. The diagnosis was made on the basis of electrocardiography data (low QRS voltage, atrial hypertrophy), echocardiography, multispiral computed tomography and magnetic resonance imaging of the heart (thickening and delayed contrasting of the endocardium, massive thrombosis of the left ventricular apex with obliteration of its cavity, encapsulated fluid in the pericardium with compression of the right ventricle). Systolic dysfunction, severe signs of restriction and arrhythmias were absent. Trombectomy, tricuspid valve plasty, pericardial resection, suturing of an open oval window were performed. Signs of active inflammation with single eosinophils, vasculitis, perimuscular sclerosis, endocardial sclerosis were detected in morphological and immunohistochemical studies of endo-, myo-, pericardium. Viral genome was not found. The therapy with methylprednisolone 24 mg/day, azathioprine 75 mg/day was started. Six months after the operation, the symptoms of heart failure are completely absent, the thrombosis did not recur.

scholarly journals Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhiro Akazawa ◽  
Manabu Taneike ◽  
Hiromichi Ueda ◽  
Rika Kitazume-Taneike ◽  
Tomokazu Murakawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Developed Countries ◽  
Left Ventricular ◽  
Negative Regulator ◽  
High Morbidity ◽  
Deficient Mice

AbstractHeart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

scholarly journals O-ring-induced transverse aortic constriction (OTAC) is a new simple method to develop cardiac hypertrophy and heart failure in mice

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasuhisa Nakao ◽  
Jun Aono ◽  
Mika Hamaguchi ◽  
Kayo Takahashi ◽  
Tomohisa Sakaue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Experimental Models ◽  
Left Ventricular ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Lung Weight ◽  
Simple Method ◽  
Fractional Shortening

AbstractSuture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator’s skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction

2000 ◽  
Vol 99 (1) ◽  
pp. 83-88 ◽  
Author(s):  
S. TALWAR ◽  
I. B. SQUIRE ◽  
P. F. DOWNIE ◽  
R. J. O'BRIEN ◽  
J. E. DAVIES ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stroke Volume ◽  
Wall Motion ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Systolic Dysfunction ◽  
The Relationship ◽  
Fractional Shortening

Cardiotrophin-1 (CT-1) is a cytokine that has been implicated as a factor involved in myocardial remodelling. The objective of the present study was to establish the relationship between circulating levels of CT-1 and measures of left ventricular size and systolic function in patients with heart failure. We recruited 15 normal subjects [six male; median age 60 years (range 30–79 years)] and 15 patients [11 male; median age 66 years (range 43–84 years)] with a clinical diagnosis of heart failure and echocardiographic left ventricular systolic dysfunction (LVSD). Echocardiographic variables (left ventricular wall motion index, end-diastolic and -systolic volumes, stroke volume, fractional shortening) and plasma CT-1 levels were determined. In patients with LVSD [median wall motion index 0.6 (range 0.3–1.4)], CT-1 was elevated [median 110.4 fmol/ml (range 33–516 fmol/ml)] compared with controls [wall motion index 2 in all cases; median CT-1 level 34.2 fmol/ml (range 6.9–54.1 fmol/ml); P < 0.0001]. Log CT-1 was correlated with log wall motion index (r = -0.76, P < 0.0001), log left ventricular end-systolic volume (r = 0.54, P < 0.05), stroke volume (r = -0.60, P = 0.007) and log fractional shortening (r = -0.70, P = 0.001). In a multivariate model of the predictors of log wall motion index, the only significant predictor was log CT-1 (R2 = 56%, P = 0.006). This is the first assessment of the relationship between plasma CT-1 levels and the degree of LVSD in humans, and demonstrates that CT-1 is elevated in heart failure in relation to the severity of LVSD.

scholarly journals Transient cytochalasin-D treatment induces apically administered rAAV2 across tight junctions for transduction of enterocytes

2008 ◽  
Vol 89 (12) ◽  
pp. 3004-3008 ◽  
Author(s):  
Ya-Yuan Fu ◽  
Eric Sibley ◽  
Shiue-Cheng Tang
Keyword(s):  
Tight Junctions ◽  
Actin Filaments ◽  
Transgene Expression ◽  
Fold Increase ◽  
Cytochalasin D ◽  
Transduction Efficiency ◽  
Intestinal Epithelial ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Virus Serotype

Enteropathogens are known to disrupt apical actin filaments and/or tight-junction barriers of intestinal epithelial cells to promote infection. In this study, we show that a controlled, cytochalasin-D (Cyto-D)-mediated disruption of actin filaments and tight junctions enhanced the apical delivery of the gene-therapy vector recombinant adeno-associated virus serotype 2 (rAAV2). This increase in transduction efficiency can be attributed to the enhanced delivery of rAAV2 across the Cyto-D disrupted tight junctions, allowing basolateral entry of rAAV2. Previously, we have shown that MG101 and doxorubicin are capable of overcoming proteasome-mediated transduction barriers of rAAV2 in enterocytes. In this study, when Cyto-D was combined with MG101 and doxorubicin in apical delivery of rAAV2 to transduce the differentiated Caco-2 enterocytes, a synergistic >2300-fold increase in transgene expression was achieved. We conclude that Cyto-D is capable of permeating the polarized enterocytes for rAAV2 transduction, which may potentially be a useful device to facilitate intestinal gene transfer via the gut lumen.

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