P1624Blockade of protease activated receptor-1 signaling attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice

Abstract Introduction Recent evidences have demonstrated that coagulation pathway is involved in cardiovascular remodeling induced by renin-angiotensin system (RAS), which finally leads to heart failure. Protease activated receptor-1 (PAR-1) is widely expressed in the vasculature and the heart, and plays important roles in pro-inflammatory process in the cardiovascular system. Recently, we demonstrated that the activity of factor Xa (FXa), which functions not only as a coagulation factor but as an agonist for PAR-1, was enhanced in renin-overexpressing hypertensive mice (Ren-Tg). Purpose The purpose of this study was to investigate whether inhibition of PAR-1 signaling has protective effects on the progression of heart failure induced by chronic RAS activation in Ren-Tg. Methods and results We treated 12–16 weeks-old male wild type mice (WT) and Ren-Tg with continuous subcutaneous infusion of PAR-1 antagonist SCH79797 (25mg/kg/day) or vehicle for 4 weeks. After treatment period, left ventricular (LV) wall thickness calculated as interventricular septum plus posterior wall thickness measured by echocardiography was greater in Ren-Tg than in WT (0.25±0.003 versus 0.18±0.002 mm), and SCH79797 attenuated the increase to 0.22±0.01 mm in Ren-Tg (both p<0.05, respectively). The ratio of heart weight to body weight was greater in Ren-Tg than in WT (6.1±0.4 versus 4.6±0.7 mg/g), and SCH79797 attenuated the increase to 5.2±0.1 mg/g (both p<0.05). The area of cardiac fibrosis evaluated by Masson-trichrome staining was greater in Ren-Tg than in WT (2.6±0.2 versus 1.4±0.3%), and SCH79797 attenuated it to 1.6±0.3% in Ren-Tg (both p<0.05). Cardiac mRNA expressions of tumor necrosis factor-α, transforming growth factor-β1, and β-myosin heavy chain were all greater in Ren-Tg than in WT, and SCH79797 attenuated the increases in Ren-Tg (all p<0.05). Conclusions Inhibition of PAR-1 signaling attenuates cardiac hypertrophy and fibrosis in Ren-Tg via inhibition of inflammatory cytokines production. These results support the involvement of PAR signaling in the development of heart failure induced by RAS, and may provide novel therapeutic insights for the treatment of hypertensive heart failure.

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Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽

10.1161/circ.132.suppl_3.14664 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Kevin Morine ◽

Vikram Paruchuri ◽

Xiaoying Qiao ◽

Emily Mackey ◽

Mark Aronovitz ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Type I Collagen ◽

Transforming Growth Factor ◽

Left Ventricular ◽

Lv Function ◽

Type I ◽

Mrna Levels ◽

Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

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A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy

PPAR Research ◽

10.1155/2018/7916953 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Si-Yu Zeng ◽

Hui-Qin Lu ◽

Qiu-Jiang Yan ◽

Jian Zou

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Wall Thickness ◽

Protective Action ◽

Pressure Overload ◽

Left Ventricular ◽

Heart Weight ◽

Hypertensive Rats ◽

Protein Levels

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 μM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy.

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Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/3714508 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Quan-wei Wang ◽

Xiao-feng Yu ◽

Hua-li Xu ◽

Xue-zhong Zhao ◽

Da-yuan Sui

Keyword(s):

Heart Failure ◽

Myocardial Fibrosis ◽

Group Treatment ◽

Transforming Growth Factor ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Left Ventricular ◽

Heart Weight ◽

Hydroxyproline Content ◽

Ginsenoside Re

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.

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

10.1101/2021.03.19.434301 ◽

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.

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Abstract 63: Reduction in Glucocorticoid Receptor Expression Attenuates Pressure Overload-induced Cardiac Hypertrophy and Promotes Heart Failure in Mice

Circulation Research ◽

10.1161/res.119.suppl_1.63 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Rongxue Wu ◽

Maura Knapp ◽

Mei Zheng ◽

James K Liao

Keyword(s):

Heart Failure ◽

Glucocorticoid Receptor ◽

Cardiac Hypertrophy ◽

Imaging System ◽

Pressure Overload ◽

Left Ventricular ◽

Receptor Expression ◽

Heart Weight ◽

Homozygous Mutation ◽

Compensatory Mechanism

Background: Left ventricular hypertrophy (LVH) is an independent risk factor for heart failure and sudden death. In addition, LVH is also a compensatory mechanism that helps the heart cope with pressure overload. Stress is considered one factor that is related to cardiac outcomes. Glucocorticoids are primary stress hormones, whose role in the heart is poorly understood. Here, we hypothesize that a reduction in the expression of the glucocorticoid receptor (GR) would decrease cardiac hypertrophy in response to pressure overload. Methods and Results: The GR homozygous mutation (GR-/-) is embryonic lethal. However, GR heterozygous mice (GR+/-) show a normal phenotype. We subjected GR+/- mice to transverse aortic constriction (TAC). At four weeks after TAC, the ratio of heart weight to tibia length increased significantly in wild-type mice (control) littermates compared with GR+/- mice. Cardiac myocyte size was also smaller in GR+/- mice vs controls, suggesting an attenuated cardiac growth response in these mice. In addition, GR+/- hearts displayed increased cell death and enhanced fibrosis in response to TAC. Cardiac function, determined by EF% and FS% (measured using the Vevo2100 imaging system), was significantly reduced in GR+/- mice compared with controls at eight weeks post-operation, while LVEDD was increased. Together, with the increased ratio of lung weight to body weight in GR+/- mice at eight weeks following TAC, this suggests an exaggerated heart failure in GR+/- mice. In vitro, hydrocortisone-induced cell growth in H9c2 cells was abolished by GR knockdown using siRNA. Finally, we looked at the mechanisms by which GR may play a role in the development of hypertrophy. We found reduced ERK-JNK activity in GR+/- hearts, suggesting that the reduced hypertrophic response in GR+/- mice occurs, at least partially, through abolished JNK and ERK activity. Conclusion: The glucocorticoid receptor is required for cardiac hypertrophy and protects the heart from heart failure during cardiac pressure overload.

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Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

Hypertension ◽

10.1161/hyp.78.suppl_1.p140 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Chandramohan Ramasamy ◽

Umadevi Subramanian ◽

Kailash N Pandey

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Growth Factor ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Left Ventricular ◽

Mutant Mice ◽

Null Mutant ◽

Wild Type

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p<0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p<0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p<0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

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Abstract 162: Cardiac Overexpression of Senescence Marker Protein 30 Inhibits Angiotensin II-Induced Cardiac Hypertrophy and Remodeling

Circulation Research ◽

10.1161/res.111.suppl_1.a162 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Tomofumi Misaka ◽

Satoshi Suzuki ◽

Makiko Miyata ◽

Atsushi Kobayashi ◽

Shu-ichi Saitoh ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Mrna Level ◽

Protective Role ◽

Left Ventricular ◽

Heart Weight ◽

Ang Ii ◽

Marker Protein ◽

Aging Effects

Backgrounds: Senescence marker protein 30 (SMP30) was originally identified as an important aging marker protein, and assumed to behave as an anti-aging factor. Previously, we demonstrated that deficiency of SMP30 exacerbates angiotensin II (Ang II)-induced reactive oxygen species (ROS) and cardiac adverse remodeling, suggesting that SMP30 may have a protective role in the heart. Thus, this study aimed to test the hypothesis that up-regulation of SMP30 inhibits cardiac hypertrophy and remodeling in response to Ang II. Methods: We generated transgenic (SMP30-TG) mice with cardiac-specific overexpression of SMP30 gene using α-myosin heavy chain promoter. SMP30-TG mice and wild type littermate (WT) were subjected to continuous Ang II infusion (800 ng/kg/min). Results: After 2 weeks, heart weight was significantly lower in SMP30-TG mice than in WT mice (P<0.01). Echocardiography revealed that calculated left ventricular mass and E/e’ were lower in SMP30-TG mice than in WT mice (P<0.01 and P<0.05, respectively), suggesting that diastolic function was preserved in SMP30-TG mice. Histological analysis showed that the degree of cardiac fibrosis was significantly decreased in SMP30-TG mice than in WT mice (P<0.05). Dihydroethidium staining demonstrated that generation of ROS was reduced in SMP30-TG mice compared with WT mice (P<0.05). Furthermore, the numbers of senescence-associated β-galactosidase-positive cardiomyocytes were decreased in SMP30-TG mice compared to WT mice (P<0.05). In addition, p21 mRNA level was significantly suppressed in SMP30-TG mice compared to WT mice (P<0.01). Conclusions: This study demonstrated cardiac-specific overexpression of SMP30 inhibits Ang II-induced cardiac hypertrophy and remodeling. These findings suggested that SMP30 has a cardio-protective role with anti-oxidative and anti-aging effects. Up-regulation of SMP30 might be a new strategy to approach senescent cardiac diseases and attenuate the development of heart failure particularly with hypertension.

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Abstract 1224: Rock1 Deletion Prevents Cardiac Dilation And Improves Contractile Function In Pathological Cardiac Hypertrophy

Circulation ◽

10.1161/circ.116.suppl_16.ii_248-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Jianjian Shi ◽

Yi-Wei Zhang ◽

Gerald W Dorn ◽

Lei Wei

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Contractile Function ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Molecular Defect ◽

Contractile Dysfunction ◽

Adrenergic Stimulation ◽

Compensatory Response

The development of left ventricular cardiomyocyte hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response. However, persistent stress eventually leads to dilated heart failure, which is a common cause of heart failure in human hypertensive and valvular heart disease. We have recently reported that ROCK1 homozygous knockout mice exhibited reduced cardiac fibrosis and cardiomyocyte apoptosis, while displayed a preserved compensatory hypertrophic response to pressure overload. Here, we tested effects of ROCK1 deficiency on cardiac hypertrophy, dilation, and dysfunction by using the transgenic Gαq mice which represent a well-characterized and highly relevant genetic mouse model of pathological hypertrophy and heart failure. We have shown that ROCK1 deletion prevented left ventricular dilation and contractile dysfunction in Gαq mice under basal condition. ROCK1 deletion also partially rescued bradycardia and improved contractile response to β-adrenergic stimulation in Gαq mice. Although the development of cardiomyocyte hypertrophy was not affected, ROCK1 deletion in Gαq mice resulted in a concentric hypertrophic phenotype associated with reduced induction of hypertrophic markers. Finally, ROCK1 deletion prevented down-regulation of type V adenylyl cyclase expression, which is a critical molecular defect contributing to the impaired β-adrenergic signaling in Gαq mice. The present study establishes for the first time a role for ROCK1 in cardiac dilation and contractile dysfunction.

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A FVII Deficiency Induces Cardiac Fibrosis in Mice Resulting in Systolic and Diastolic Dysfunction.

Blood ◽

10.1182/blood.v110.11.1747.1747 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1747-1747

Author(s):

Haifeng Xu ◽

Mayra Sandoval-Cooper ◽

Deborah L. Donahue ◽

Victoria A. Ploplis ◽

Francis J. Castellino

Keyword(s):

Cardiac Function ◽

Cardiac Fibrosis ◽

Inflammatory Responses ◽

Coagulation Factor ◽

Restrictive Cardiomyopathy ◽

Left Ventricular ◽

Heart Weight ◽

Mrna Levels ◽

Wild Type ◽

Fvii Deficiency

Abstract Mice severely deficient in coagulation Factor (F)VII that survive to adulthood have been developed, thus allowing the study of spontaneous bleeding and inflammatory phenotypes under conditions of a deficiency of extrinsic coagulation, especially in organs e.g., the heart, that continually undergo normal mechanical challenge. Mice genetically modified to produce very low levels (∼1% of wild-type) of coagulation FVII (FVIItTA/tTA) spontaneously developed heart abnormalities that were revealed by echocardiography. There were no significant differences between groups at baseline for the hemodynamic and respiratory parameters: temperature and heart rate (HR). The end-systolic functions of FVIItTA/tTA mice heart were comparable to wild-type (WT) controls. However, there were significant changes in the end-diastolic parameters of FVIItTA/tTA hearts. The diameter at end-diastole in FVIItTA/tTA mice was smaller compared to WT mice, which was due to the stiffness of the interventricular wall. When viewed from the parasternal short-axis, these mice had evidence of hypokinesis, indicating alteration of the elastic properties of the left ventricular (LV) wall. Correspondingly, the stroke volume, ejection fraction, fractional shortening, and cardiac output were lower in FVIItTA/tTA mice, compared to WT mice. Mitral valve inflow was compromised in FVIItTA/tTA mice, as demonstrated by the reduced early/late (E/A) filling ratio. We found that the spontaneous impaired cardiac function in FVIItTA/tTA mice was associated with an increased ratio of heart weight to body weight. Decreases in ventricular size, accompanied by reductions in systolic and diastolic functions, suggest a restrictive cardiomyopathy, consistent with an infiltrative myopathic process. Microscopic analysis of mouse hearts showed severe patchy fibrosis in FVIItTA/tTA mice. Hemosiderin deposition in hearts of these mice, along with large increases in inflammatory cells, ultimately resulting in widespread collagen deposition, were found. Significant increases in mRNA levels of TGF-beta, TNF-alpha, and a variety of matrix metalloproteinases, beginning at early ages in FVIItTA/tTA mice, supported the fibrotic pathology. The results of this study demonstrated that hemorrhagic and inflammatory responses to a severe FVII deficiency resulted in the development of cardiac fibrosis, manifest echocardiographically as a restrictive cardiomyopathy, with significantly compromised ventricular diastolic and systolic functions. These data also suggest that a FVII deficiency differentially regulates the expression level of inflammation and extracellular matrix proteins, which result in compromised cardiac function.

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Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin

Cardiovascular Research ◽

10.1093/cvr/cvz016 ◽

2019 ◽

Vol 116 (1) ◽

pp. 101-113 ◽

Cited By ~ 4

Author(s):

Hairuo Lin ◽

Yang Li ◽

Hailin Zhu ◽

Qiancheng Wang ◽

Zhenhuan Chen ◽

...

Keyword(s):

Heart Failure ◽

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Weight Ratio ◽

Left Ventricular ◽

Neonatal Rat ◽

Cardiac Remodelling ◽

Heart Weight ◽

Body Weight Ratio

Abstract Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

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