Abstract P136: E2F2/4 Regulated by Serine 21 Phosphorylation of GSK-3α Play Compensatory Roles During Pressure Overload

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Takanobu Yamamoto ◽  
Yasuhiro Maejima ◽  
Peiyong Zhai ◽  
Takahisa Matsuda ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Causative Role ◽  
Serine Threonine Kinase ◽  
Lv Dysfunction ◽  
Cardiac Phenotype ◽  
And Function

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with two isoforms, alpha and beta, which have distinct functions in cardiomyocytes (CMs). GSK-3alpha is phosphorylated at S21 during pressure overload (PO), and inhibition of S21 phosphorylation in GSK-3alpha S21A knock-in (alpha−KI) mice promotes hypertrophy and heart failure in response to PO, accompanied by decreases in the total number of CMs in the heart. Since GSK-3alpha downregulates cyclinD1 in the nucleus, GSK-3alpha may negatively regulate E2F-mediated transcription. Reporter gene assays showed that the transcriptional activity of E2F was increased by GSK-3alpha knockdown (1.75 fold, p<0.05). To evaluate the role of E2F isoforms in regulating cardiac hypertrophy and function during PO, E2F1−/−, E2F2−/+, E2F4−/+, and wild type (WT) mice were subjected to transverse aortic constriction (TAC). Left ventricular (LV) weight/ tibial length (LVW/TL) was significantly greater and LV ejection fraction (LVEF) was significantly decreased in both E2F2−/+ and E2F4−/+ after 2 weeks of TAC (LVW/TL: E2F2−/+=7.1±0.3, E2F4−/+=7.0±0.4, WT=5.9±0.3, p<0.05 vs. WT; LVEF: E2F2−/+=53±1%, E2F4−/+=61±2%, WT=75±1%, p<0.05 vs. WT). Thus, downregulation of either E2F2 or E2F4 induced a phenotype similar to that of alpha−KI in response to TAC. To examine the causative role of E2F2/E2F4 downregulation in mediating the cardiac phenotype in alpha-KI mice, adenovirus (Ad) harboring either E2F2 or E2F4 was injected into alpha-KI hearts. Rescue with E2F2 or E2F4 attenuated cardiac hypertrophy (LVW/TL: alpha−KI+E2F2=7.1±0.4, alpha−KI+E2F4=7.3±0.3, alpha−KI+LacZ=8.7±0.4, p<0.05 vs. alpha−KI+LacZ) and improved LV dysfunction (LVEF: alpha−KI+E2F2=66±3%, alpha−KI+E2F4=60±2%, alpha−KI+LacZ=39±2%, p<0.05 vs. alpha−KI+LacZ) in alpha−KI mice under PO conditions. Injection of either Ad-E2F2 or Ad-E2F4, but not of Ad-LacZ, significantly increased the number of Ki67-positive myocytes in the alpha-KI mice (alpha-KI+LacZ =0.7±0.3%, alpha-KI+E2F2=10.4±2.3%, alpha-KI+E2F4=9.2±1.5%, p<0.05 vs. alpha-KI+LacZ). These results suggest that maintaining the activity of E2F2 and E2F4 through S21 phosphorylation of GSK-3alpha plays an essential role in preserving cardiac function during PO.

scholarly journals Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca 2+ Handling After Pressure Overload

Circulation ◽  
2020 ◽  
Vol 141 (3) ◽  
pp. 199-216 ◽  
Author(s):  
Fiona Bartoli ◽  
Marc A. Bailey ◽  
Baptiste Rode ◽  
Philippe Mateo ◽  
Fabrice Antigny ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Specific Expression ◽  
Channel Inhibition

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. Results: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. Conclusions: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

Abstract 18122: Mir-206 Plays an Important Role in Mediating Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Sebstiano Sciarretta ◽  
Yanfei Yang ◽  
Dominic P Del Re ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Sequence Similarity ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Mouse Heart ◽  
Sham Operation ◽  
Hippo Signaling ◽  
Qrt Pcr

Introduction: Expression of miR-206 is upregulated by YAP, a key transcription co-factor controlled by the Hippo signaling pathway, and mediates YAP-induced hypertrophy and survival of cardiomyocytes. Although miR-206 is known to promote hypertrophy of skeletal muscle, the role of miR-206 in the heart under clinically relevant conditions in vivo remains unknown. We investigated the role of miR-206 in mediating cardiac hypertrophy in response to pressure overload (PO). Results: The level of miR-206 in the mouse heart, as evaluated by qRT-PCR, was upregulated 2.9 fold (p<0.05) 7 days after transverse aortic constriction (TAC) compared to sham operation. In order to evaluate the involvement of miR-206 in cardiac hypertrophy, wild-type C57B/6J mice were administered LNA inhibitor designed to selectively inhibit miR-206, or control scrambled LNA, by tail vein injection. Specificity of the LNA inhibitor was confirmed by qRT-PCR analysis of miRNA expression 48 hours after treatment. Notably, the LNA inhibitor did not affect the level of miR-1, which has a sequence similarity with miR-206. After 48 hours, mice from both treatment groups were subjected to sham operation or TAC. After 7 days of TAC, echocardiography was performed and mice were sacrificed. Upregulation of myocardial miR-206 expression levels after 7 days TAC observed in LNA control-treated mice was completely abolished in LNA-anti-206 -treated mice. A significant increase in left ventricular weight/tibial length (mg/mm) in LNA control-treated mice following TAC was observed (sham vs TAC: 3.7, 4.8, p<0.05); however, no increase was observed in LNA-anti-206 -treated mice (3.8, 3.8). We also noted significant differences in chamber wall thickness (mm) between the LNA-control and LNA-anti-206-treated TAC groups (diastolic posterior wall 0.91, 0.61, p<0.05). Additionally, cardiomyocyte cross sectional area (1.23, 0.9, p<0.05) and ANF expression (2.5, 1.3, P<0.05) were significantly increased in the LNA control-treated TAC group, and these responses were attenuated in the LNA-anti-206-treated mice. Conclusions: These data demonstrate that inhibition of miR-206 impairs PO-induced hypertrophy and indicates that miR-206 is an important endogenous mediator of heart growth in response to PO.

Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat

1996 ◽  
Vol 271 (5) ◽  
pp. H1978-H1987 ◽  
Author(s):  
Y. Ishibashi ◽  
H. Tsutsui ◽  
S. Yamamoto ◽  
M. Takahashi ◽  
K. Imanaka-Yoshida ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Contractile Function ◽  
Pressure Overload ◽  
Progressive Increase ◽  
Left Ventricular ◽  
Contractile Dysfunction

We have shown that increased microtubules cause myocyte contractile dysfunction in feline right ventricular pressure-overload hypertrophy. To investigate the association between the progression of cardiac hypertrophy and microtubules and to delineate the role of microtubules in contractile defects in hypertrophied myocytes, we assessed the amounts of free and polymerized tubulin proteins, using Western blot analysis and immunofluorescence micrograph, and evaluated the sarcomere mechanics of myocytes isolated from rats with pressure-overload left ventricular (LV) hypertrophy. Total and polymerized tubulins were progressively and persistently increased in LV after the imposition of pressure overload. The increase in microtubules was associated with the development and progression of hypertrophy and not the immediate response to the stress loading to the myocardium. The contractile function of hypertrophied myocytes was depressed in parallel with the increase in microtubules. Depolymerization of microtubules normalized the initially depressed LV myocyte contractile function. Thus the progressive increase of microtubule density during LV hypertrophy due to persistent pressure overloading to the myocardium may cause the consequent myocyte contractile dysfunction.

scholarly journals HMGB1 Aggravates Pressure Overload-Induced Left Ventricular Dysfunction by Promoting Myocardial Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lei Zhang ◽  
Ying Yu ◽  
Peng Yu ◽  
Jian Wu ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
High Mobility ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Lv Dysfunction

Aim. Fibrosis had important effects on pressure overload-induced left ventricular (LV) dysfunction. High-mobility group box 1 (HMGB1), which was closely associated with fibrosis, was involved in the pressure overload-induced cardiac injury. This study determines the role of HMGB1 in LV dysfunction under pressure overload. Methods. Transverse aortic constriction (TAC) operation was performed on male C57BL/6J mice to build the model of pressure overload, while HMGB1 or PBS was injected into the LV wall. Cardiac function, collagen volume, and relevant genes were detected. Results. Echocardiography demonstrated that the levels of LV ejection fraction (LVEF) were markedly decreased on day 28 after TAC, which was consistent with raised collagen in the myocardium. Moreover, we found that the exposure of mice to TAC + HMGB1 is associated with higher mortality, BNP, and collagen volume in the myocardium and lower LVEF. In addition, real-time PCR showed that the expression of collagen type I, TGF-β, and MMP2 markedly increased in the myocardium after TAC, while HMGB1 overexpression further raised the TGF-β expression but not collagen type I and MMP2 expressions. Conclusion. This study indicated that exogenous HMGB1 overexpression in the myocardium aggravated the pressure overload-induced LV dysfunction by promoting cardiac fibrosis, which may be mediated by increasing the TGF-β expression.

Abstract 69: Cardiomyocyte GSK-3α Signaling Exacerbate Pressure Overload-induced Dilated Cardiomyopathy and Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Firdos Ahmad ◽  
Hind Lal ◽  
Vipin K Verma ◽  
Qinkun Zhang ◽  
James R Woodgett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Tamoxifen Treatment ◽  
Control Group ◽  
Lv Remodeling

Chronic pressure-overload (PO) induced-dilated cardiomyopathy (DCM) is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of glycogen synthase kinase-3α (GSK-3α) in PO-induced remodeling is not clear and existing dataset with global transgenic and knockout (KO) models show opposing roles. We sought to identify the specific role of GSK-3α in PO-induced dilatative cardiac remodeling. To better understand the role of GSK-3α, we employed cardiomyocyte-specific GSK3A ( GSK3A fl/fl MerCreMer ) KO mice. Post-tamoxifen treatment, the GSK-3α KO and littermate control mice underwent sham or trans-aortic constriction (TAC) surgery. Heart function was assessed at 0, 2, 4 and 6 week post-TAC using serial M-mode echocardiography. Cardiac function in the KOs and littermate controls declines equally up to 2 weeks of TAC. At 4 week, KO hearts underwent further hypertrophy, retaining concentric LV remodeling and preserved contractile function both at systole and diastole. In contrast, wild-type LV showed significant chamber dilatation with an impaired contractility. Significantly reduced LV chamber dilatation [LVIDd(mm); 5.4±0.4 vs. 4.9±0.4, P =0.01] and preserved contractile function [LVEF(%); 22.2±12.6 vs. 40.0±18.7, P =0.02] remains same in the KO mice until the end of the study (6 wk). Furthermore, LV posterior wall thickness in the KO hearts, both at systole and diastole, were significantly greater in comparison to the controls. Consistent with preserved LV dimension, significantly less mortality was observed in the KO vs. control group during the remodeling phase. Histological analysis of heart sections further revealed better preserved LV chamber and protection against TAC-induced cellular hypertrophy in the GSK-3α KOs. Moreover, KO hearts showed significantly less fibrosis accompanied with low level of cardiomyocyte apoptosis post-6 wk of TAC. Taken together, these observations show that cardiomyocyte-specific deletion of GSK-3α protects against chronic PO-induced adverse LV remodeling and preserves contractile function. Inhibiting specifically GSK-3α using isoform-specific inhibitor could be a viable therapeutic strategy to limit the PO-induced DCM, adverse remodeling and heart failure.

scholarly journals How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial

2017 ◽  
Vol 313 (5) ◽  
pp. H919-H930 ◽  
Author(s):  
Mordecai P. Blaustein
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Wild Type ◽  
Ouabain Binding ◽  
Transaortic Constriction ◽  
Endogenous Ouabain

Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive α2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of α2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α2-ouabain-resistant (R) mice in which the normally ouabain-resistant α1-Na+ pumps were mutated to an ouabain-sensitive (S) form (α1S/Sα2R/R or “SWAP” vs. wild-type or α1R/R α2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease.

Abstract 13114: P22 phox Protects the Heart Against Pressure Overload

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yasuki Nakada ◽  
Wataru Mizushima ◽  
Yanfei Yang ◽  
Peiyong Zhai ◽  
Shinichi Oka ◽  
...  
Keyword(s):  
Control Mouse ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Sham Operation ◽  
Cysteine Oxidation ◽  
Isolated Cardiomyocytes ◽  
Ventricular Ejection Fraction ◽  
Cardiac Phenotype

Introduction: p22 phox forms a complex with NADPH oxidases, major sources of O 2 - and H 2 O 2 . However, the role of p22 phox during stress remains to be elucidated. Purpose: To investigate the role of endogenous p22 phox during pressure overload (PO). Methods and Results: The level of p22 phox protein in isolated cardiomyocytes after 4 weeks of transverse aortic constriction (TAC) was significantly higher than after sham operation (1.7-fold, p<0.05). The cardiac phenotype of cardiac-specific p22 phox knockout ( p22 phox cKO) mice was normal at baseline. However, four weeks after TAC, p22 phox cKO mice exhibited a lower left ventricular ejection fraction (32.0±10.0 vs 53.2±8.4%, p<0.05), a higher lung weight to tibial length ratio (23.0±6.0 vs 13.1±6.6, p<0.05), and more interstitial fibrosis (6.1±1.0 vs 4.4±1.1%, p<0.05) than control mice, indicating that the loss of p22 phox exacerbates TAC-induced cardiac dysfunction. The level of oxidative stress in the heart, evaluated by dityrosine immunoblot, was significantly lower in p22 phox cKO mice than in control mice (0.71±0.04 vs 1.00±0.04, p<0.01). The peak Ca 2+ amplitude in isolated cardiomyocytes was lower in p22 phox cKO mice than in control mice at baseline (2.4±0.1 vs 3.0±0.2, p<0.01). Although mRNA expression of SERCA2a did not differ, there was significantly less SERCA2a protein in p22 phox cKO mice than in control mice (0.62±0.10 vs 1.00±0.23, p<0.01) at baseline. The amount of biotinylated iodoacetamide labeled SERCA2a was significantly smaller in p22 phox cKO hearts than in control mouse hearts (0.4-fold, p<0.01), indicating that cysteine residues in SERCA2a are oxidized to a greater extent in p22 phox cKO hearts than in control mouse hearts. Since cysteine oxidation decreases the stability of SERCA2a, our results suggest that p22 phox stabilizes SERCA2a by preventing cysteine oxidation. Conclusions: Endogenous p22 phox is protective against PO, possibly by maintaining SERCA2a stability.

Abstract 312: STIM1 And The Development Of Pressure-overload Induced Cardiac Hypertrophy In Rodents

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Aortic Pressure ◽  
Cellular Level ◽  
Left Ventricular ◽  
Cross Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We studied the role of STIM1 in a pressure-overload induced cardiac hypertrophy model in mice. We observed that STIM1 cardiac expression is increased during left ventricular hypertrophy (LVH) induced by Transverse Aortic Constriction (TAC). We then used recombinant Associated Adenovirus 9 (AAV9) to perform cardiac-targeted gene silencing in vivo. C57Bl/6 mice were injected with saline (noAAV) or with AAV9 expressing shRNA against STIM1 (shSTIM1) at the dose of 1e+11 viral genome which resulted in 70% decrease of STIM1 cardiac expression compared to control mice. Three weeks later, TAC was performed and mice were studied three other weeks later. We found that TAC-shSTIM1 treated mice did not develop LVH compared to noAAV despite the same increase in aortic pressure. Echocardiographic and hemodynamic measurements (see table) showed that TAC-shSTIM1-treated mice had LV dilation and a decreased left ventricular contractile function in line with the absence of compensatory LVH in these mice. Immunohistochemistry demonstrated that LVH prevention was observed at the cellular level with cardiac myocytes cross-section area comparable to sham littermates however with a trend towards more interstitial fibrosis. This study reveals the essential role of STIM1 in the development of compensatory LVH in mice.

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