Oleanonic acid ameliorates pressure overload-induced cardiac hypertrophy in rats: The role of PKCζ-NF-κB pathway

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

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Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽

10.1161/hyp.68.suppl_1.026 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Hongliang Li ◽

Peng Zhang

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

Pressure Overload ◽

Adaptor Protein ◽

Negative Regulator ◽

Akt Inhibitor ◽

Aortic Banding ◽

Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

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Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart

Circulation Research ◽

10.1161/res.109.suppl_1.ap189 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Davy Vanhoutte ◽

Jop Van Berlo ◽

Allen J York ◽

Yi Zheng ◽

Jeffery D Molkentin

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Small Gtpase ◽

Mouse Heart ◽

Activity Levels ◽

Lung Weight ◽

Pathological Cardiac Hypertrophy ◽

Rhoa Protein

Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy. Methods and results . Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoA flx/flx ) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoA βMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoA βMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoA βMHC-cre versus 7.7 ± 0.4 for RhoA flx/flx ; and cardiomyocyte size (mm 2 ): 407 ± 21 for RhoA βMHC-cre versus 262 ± 8 for RhoA flx/flx ; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoA βMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoA βMHC-cre versus 29.3 ± 1.2 for RhoA flx/flx ; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion. Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.

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Abstract 282: Role of a Disintegrin and Metalloproteinase 15 in Cardiac Hypertrophy and Fibrosis Following Pressure Overload

Circulation Research ◽

10.1161/res.127.suppl_1.282 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Priya Aujla ◽

Sayantan Jana ◽

Michael Chute ◽

Zamaneh Kassiri

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Cell Function ◽

Systolic Function ◽

Mechanical Strain ◽

Pressure Overload ◽

Compensatory Hypertrophy ◽

Hypertrophic Response ◽

A Disintegrin And Metalloproteinase

Introduction: Disintegrin and metalloproteinases (ADAMs) are membrane-bound cell surface enzymes that are capable of both proteolytic functions (via the metalloproteinase domain) and adhesive functions (via the disintegrin domain), whereby they can influence cell function and extracellular matrix (ECM) remodelling in the heart. ADAM15 is unique among the ADAMs, as it is also capable of degrading ECM proteins. ADAM12 and ADAM17 have been reported to regulate cardiac hypertrophy, but the role of ADAM15 in cardiac hypertrophy is not known. This study investigates the role of ADAM15 in cardiac hypertrophy and fibrosis following pressure overload. Methods & Results: Genetically modified male ADAM15-deficient ( Adam15 -/- ) and wildtype (WT) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC). Cardiac function and structural remodelling were assessed using echocardiography at 2-, and 6-wks post-TAC. Hearts were excised at 2-, or 6-wks post-TAC. Adam15 -/- hearts presented greater hypertrophy and decreased cardiac systolic function at 6wks post-TAC, but no difference at 2wks post-TAC compared to WT-TAC mice. Adam15 -/- hearts also showed exacerbated fibrosis at 6wks post-TAC, but not at 2wks post-TAC, compared to WT. Mechanical strain (i.e. pressure overload) triggers two temporally activated pathways leading to an initial compensatory hypertrophy, which can culminate to decompensation and dilated cardiomyopathy. Consistent with the greater hypertrophy, phosphorylation of ERK1/2, JNK1/2/3, and GSK3β was increased in Adam15 -/- mice. The calcineurin-NFAT pathways can mediate pressure overload-induced hypertrophy, but we found that Adam15-deficiency did not impact this pathway. The mechanism responsible for this function of ADAM15 requires further investigation. Conclusion: This study reports a novel cardioprotective function for ADAM15 in pressure overload, where loss of ADAM15 promotes cardiac fibrosis and decompensated cardiac hypertrophy but does not alter the compensated hypertrophic response.

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

Circulation ◽

10.1161/circulationaha.118.038891 ◽

2020 ◽

Vol 141 (3) ◽

pp. 199-216 ◽

Cited By ~ 5

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.

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Role of the V1 vasopressin receptor in pressure overload-induced cardiac hypertrophy

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2007.03.090 ◽

2007 ◽

Vol 42 (6) ◽

pp. S32

Author(s):

David L. Crandall ◽

Viera Kasparcova ◽

Hillary M. Semus ◽

George P. Vlasuk ◽

Orlando P. Bueno

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Vasopressin Receptor

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The endothelium-dependent effect of RTEF-1 in pressure overload cardiac hypertrophy: role of VEGF-B

Cardiovascular Research ◽

10.1093/cvr/cvq400 ◽

2010 ◽

Vol 90 (2) ◽

pp. 325-334 ◽

Cited By ~ 16

Author(s):

Ming Xu ◽

Yi Jin ◽

Qinhui Song ◽

Jiaping Wu ◽

Melissa J. Philbrick ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Dependent Effect

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Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽

10.1161/circ.142.suppl_3.16205 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Kisuk Min ◽

Yan Huang ◽

Frank J Giordano ◽

Sudip Bajpeyi ◽

Anton M Bennett

Keyword(s):

Heart Failure ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Cardiac Muscle ◽

Molecular Mechanisms ◽

Weight Ratio ◽

Pressure Overload ◽

Body Weight Ratio ◽

Pathological Cardiac Hypertrophy

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.

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

Circulation ◽

10.1161/circ.132.suppl_3.18122 ◽

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.

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Abstract 72: Pka Is A Master Regulator Of Pathological Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.115.suppl_1.72 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Xiaoying Zhang ◽

Ying LI ◽

Mingxin Tang ◽

Xiaojie Ai ◽

Christopher Szeto ◽

...

Keyword(s):

Protein Synthesis ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Surface Area ◽

Myocardial Fibrosis ◽

Pressure Overload ◽

Sectional Area ◽

Cross Sectional ◽

Pathological Cardiac Hypertrophy

Aims: The role of PKA in pathological cardiac hypertrophy (PCH) is not clear. The literature suggests both prohypertrophic and antihypertrophic effects of PKA. Furthermore, there are endogenous PKA inhibitors, PKI, highly expressed in the heart to regulate PKA activity but their roles in PCH have not been studied. We aim to explore the role of PKI/PKA in PCH induced by isoproterenol, phenylephrine, angiotensin II and pressure overload. Methods and Results: 1. PKIα and PKIγ were highly expressed in the heart but only PKIα was reduced by transaortic banding (TAB); TAB induced a significant increase in cardiac PKA activity at 1 week post TAB. 2. Four transgenic mouse lines with high (HE), medium (ME), low (LE) and very low (VLE) expression of PKI-GFP were obtained with the inhibition of maximum PKA activity induced by 1μM cAMP by 95%, 57%, 20% and 10% in the cardiac homogenates; 3. In the VLE hearts, some myocytes were PKI-GFP+ and some were PKI-GFP-, GFP- LVMs had significantly larger surface area than GFP+ LVMs; 4. PKA inhibition by PKI-GFP abolished PCH induced by isoproterenol, phenylephrine, angiotensin II in HE mice; 5. TAB for 8 weeks did not change HW/BW, myocyte cross-sectional area and myocardial fibrosis in HE mice but induced significant increases in HW/BW, myocyte cross-sectional area, myocardial fibrosis and depressed cardiac fractional shortening in control mice. 6. In cultured neonatal rat ventricular myocytes, PKI-GFP prevented myocyte hypertrophy induced by isoproterenol (ISO), phenylephrine (PE) and angiotensin II, as evidenced by no significant increases in protein synthesis (protein/DNA ratio), myocyte surface area, sarcomere organization. 7. PKI-GFP in NRVMs prevented the translocation of NFAT3 and HDAC5 induced by ISO and PE and increased the secretion of antihypertrophic ANF at baseline; 8. TAB induced PKA-dependent phosphorylation of GSK-3α and GSK-3β, inactivating them to relieve their antihypertrophic effect and promote protein synthesis (increased phosphorylation of mTORC1, eIF-4EBP1, p70 S6K); PKA inhibition abolished these effects. Conclusions: PKA is regulated by PKI and is a master regulator of PCH induced by pressure overload.

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