Abstract 542: Mice with Cardiomyocyte-Restricted IGF-1 Receptor Deletion Exhibit Diminished Cardiomyocyte Size and Resistance to Exercise-Induced Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jaetaek Kim ◽  
Adam R Wende ◽  
Crystal Sloan ◽  
Benjamin E Wayment ◽  
Sheldon E Litwin ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Development ◽  
Systolic Function ◽  
Fold Increase ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Receptor Signaling ◽  
Cross Sectional ◽  
Akt Phosphorylation ◽  
Physiological Cardiac Hypertrophy

Insulin-like growth factor 1 (IGF-1) and IGF-1 receptors are expressed in murine hearts, and IGF-1 receptor signaling in cardiac muscle has been proposed to play a role in growth, differentiation, and cell survival, but mechanisms by which IGF-1 modulates myocardial structure and function are only partially understood. To investigate the role of IGF-1 signaling on cardiac development and physiology, we generated mice with cardiomyocyte-restricted knockout of the IGF-1receptor (IGF-1R −/−) by crossing α-MHC-Cre mice with mice containing a floxed exon 3 of the IGF-1R gene. Ablation of IGF-1 receptors in cardiomyocytes did not alter baseline heart weight to tibia length (HW/TL) ratios at 8 weeks or 12 weeks of age. However, wheat germ agglutinin (WGA-FITC) staining revealed that myocyte cross-sectional area was reduced by 18.8% (P < 0.05). To define the contribution of IGF-1 receptor signaling in the development of physiological hypertrophy; mice [WT (n = 7) or IGF-1R −/− (n = 9)] were subjected to 4 weeks swim (Sw) training and compared with Sedentary (Sed) wild type (WT) (n = 5) or IGF-1R −/− (n = 7) mice. HW/TL ratios increased by 19.2% in WT animals after swim training (5.19 ± 0.26 vs. 6.18 ± 0.2, P < 0.05), but only by 5.5% in Sw IGF-1R −/− mice (5.58 ± 0.18 vs. 5.89 ± 0.22, P = 0.32) and the fold increase in HW/TL was significantly greater in Sw WT vs. Sw IGF-1R −/− (P < 0.05). Despite resistance to hypertrophy, cardiac systolic function assessed by ejection fraction was preserved in Sw IGF-1R −/− (before Sw 0.71 ± 0.02 vs. after Sw 0.67 ± 0.02, P = 0.12). Phosphorylation of Akt was significantly increased in both trained WT and IGF-1R−/− mice at Ser473 [fold-change 1.61 ± 0.09 (P < 0.05) and 2.11 ± 0.19 (P < 0.01), respectively] and Thr308 [2.42 ± 0.24 and 2.61 ± 0.59 (P < 0.01), respectively] vs. Sed. Surprisingly Ser (473) Akt phosphorylation was greater in Sw IGF-1R−/− vs. Sw WT (P < 0.05). These data define an essential role for IGF-1 signaling in mediating physiologic cardiomyocyte hypertrophy, and indicate that although Akt signaling might be necessary for mediating physiological cardiac hypertrophy it is not sufficient in the absence of myocardial IGF-1R signaling.

scholarly journals Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoying Zhang ◽  
Zhiying Zhang ◽  
Pengxiang Wang ◽  
Yiwei Han ◽  
Lijun Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Metabolism ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Weight Ratio ◽  
Tibetan Medicine ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Body Weight Ratio ◽  
Cross Sectional

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K

2021 ◽  
Author(s):  
Kate L. Weeks ◽  
Yow Keat Tham ◽  
Suzan G. Yildiz ◽  
Yonali Alexander ◽  
Daniel G. Donner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Exercise Induced ◽  
Physiological Hypertrophy ◽  
Constitutively Active

The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110a (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy, and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor which regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training, or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3KTg+). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (~21%) in heart weight normalized to tibia length vs untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression, but was comparable between genotypes. However, differences in Foxo3a, Hsp70 and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3KTg+ mice. Cardiac Akt and FoxO1 protein expression were significantly reduced in hearts of caPI3KTg+ mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when considering FoxO1 as a target for treating the diseased heart.

Abstract 260: Systemic Loss of p62 Reduces Pressure Overload Induced Cardiac Hypertrophy, Dysfunction and Apoptosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Mannix Auger-Messier ◽  
Khosrow Rezvani ◽  
Scott Pattison
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Wild Type ◽  
Protein Aggregate ◽  
Cross Sectional ◽  
Post Surgery ◽  
Deficient Mice

Introduction: p62 is a pleiotropic protein with defined roles in TNFα signaling, protein aggregate formation, and protein degradation processes. Current data suggest that p62 is a stress-response protein, with increased protein levels reported in TAC, MI, I/R, and protein aggregation models of cardiac disease. To date, there has been little study on the gain- or loss- of p62 function in cardiomyocyte/cardiac pathology. Our preliminary data found that adenoviral overexpression of p62 caused cardiomyocyte hypertrophy and cytotoxicity and that p62 was upregulated by pressure-overload stress. Hypothesis: Loss of p62 will be cardioprotective against pressure-overload pathology. Methods: Systemic p62 knockout mice underwent sham or transverse-aortic constriction surgery and were studied longitudinally to 8 weeks post-surgery by echocardiography. Results: Hearts from p62-null mice had significantly preserved cardiac function (%Fractional Shortening) over wild-type controls. p62-deficient mice had significantly less cardiac hypertrophy (heart weight/body weight ratios and myofiber cross-sectional areas) and showed no chamber dilation (LVED) in response to pressure-overload stress, unlike wild-types. Hearts from wild-type mice showed pronounced fibrotic remodeling and induction of apoptosis (TUNEL), while p62 knockouts had significantly less collagen staining and no evidence of apoptotic stimulation. Overexpression of p62 in rat neonatal cardiomyocytes significantly inhibited proteasomal catalytic activities (>50%) and showed increased indices of cardiomyocyte cell death. Conclusion: Our data show that induction of p62 is deleterious in vitro and that loss of p62 imparts cardioprotection against hemodynamic stress in vivo . The beneficial phenotype observed in hearts from p62-deficient mice may be due to p62-dependent mechanisms responsible for proteasomal dysfunction and apoptosis activation.

scholarly journals KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yi Wang ◽  
Hongjuan Liao ◽  
Yueheng Wang ◽  
Jinlin Zhou ◽  
Feng Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Western Blot ◽  
Real Time ◽  
Real Time Pcr ◽  
Mtor Signaling ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr

Abstract Background Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy. Methods Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR. Results The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy. Conclusions Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

Abstract 182: CTRP9 - A Novel Cardiac Derived Secreted Factor With Anti-hypertrophic Properties

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Astrid H Breitbart ◽  
Florian Brandes ◽  
Oliver Müller ◽  
Natali Froese ◽  
Mortimer Korf-Klingebiel ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Real Time ◽  
Real Time Pcr ◽  
Weight Ratio ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Quantitative Real Time Pcr ◽  
Rat Cardiomyocytes ◽  
Knock Out

Background: CTRP9 (also called C1qtnf9) is a newly discovered secreted protein and a paralog of adiponectin. The biological functions of CTRP9, however, are still largely unknown. Results: Although previous data from a semi-quantitative real-time PCR had suggested that CTRP9 is mainly secreted by adipose tissue, we found its mRNA to be predominantly expressed in the heart by quantitative real-time PCR. Interestingly, we identified CTRP9 mRNA as significantly upregulated in hypertrophied mouse hearts (after 2 weeks of aortic constriction, TAC) as well as in hypertrophied human hearts (24±4-fold versus healthy human myocardium; p<0.01). LacZ staining in myocardial sections of C1qtnf9 tm1(KOMP)Vlcg mice (knock-out for CTRP9, containing a lacZ cassette to replace exon 1-3 of the gene) revealed exclusive expression of CTRP9 in capillary and venous endothelial cells. Adenoviral overexpression of CTRP9 or recombinant CTRP9 strongly inhibited cardiomyocyte hypertrophy (assessed as cell size, protein/DNA-ratio, expression of skeletal α-actin) after stimulation with phenylephrine (PE). Accordingly, myocardial overexpression of CTRP9 via a cardioselective adeno-associated virus (AAV9-CTRP9) in mice dramatically reduced cardiac hypertrophy after two weeks of pressure overload (heart weight/body weight ratio, HW/BW in mg/g: AAV9-control 6.5±0.2 versus AAV9-CTRP9 5.6±0.2; p<0.01). In turn, downregulation of CTRP9 by a specific siRNA aggravated cardiomyocyte growth in response to PE in vitro and CTRP9 knock-out (KO) mice exerted an enhanced hypertrophic response after two weeks of TAC in vivo (% increase in HW/BW versus sham: wild-type 77±13, KO 106±9; p<0.05). Mechanistically, we found that CTRP9 binds to the adiponectin receptor 1 (AdipoR1) and inhibits prohypertrophic mTOR signalling in cardiac myocytes. SiRNA mediated downregulation of AdipoR1 or mTOR in neonatal rat cardiomyocytes abolished the anti-hypertrophic effect of CTRP9. Conclusion: Endothelial cell derived CTRP9 inhibits cardiac hypertrophy through binding to AdipoR1 and inhibition of the mTOR pathway in cardiomyocytes. Therefore, myocardial application of CTRP9 could be a novel strategy to combat pathological cardiac hypertrophy.

Abstract P112: Estradiol Induces Physiological Hypertrophic Growth in the Healthy Mouse Heart

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Ba Tiep Nguyen ◽  
Hubertus Jarry ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Weight Ratio ◽  
Treated Group ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Mouse Heart ◽  
Cross Sectional ◽  
Hypertrophic Growth ◽  
Protein Levels ◽  
Cycle Regulation

Estradiol-17beta (E2) has been shown to exert anti-hypertrophic actions by either attenuating or blunting the development of left ventricular hypertrophy. However, the vast majority of these studies have been performed in stressed or diseased hearts. Consequently, very little is known about the actions of E2 in the stress- and disease-free heart. The aim of our study was to identify and characterize structurally and molecularly the role of E2 in the healthy heart. Female C57Bl/6J mice were ovariectomized at the age of two months. Mice were randomly assigned into groups feeding on either an E2-containing (n = 19) or soy-free (Ctrl; n = 19) diet for three months. Following this, all mice were sacrificed and hearts were collected for weight measurement. Left ventricles were analyzed structurally by immunohistochemistry and molecularly by genome-wide expression profiling. E2 led to an increase in the heart weight (11%; P < 0.001) and the heart-to-body weight ratio (32%; P < 0.001) compared to Ctrl mice. Cardiomyocyte cross-sectional area revealed cardiomyocyte hypertrophy in E2 (n = 6) compared to Ctrl (n = 5) mice (32%; P = 0.004). Analysis of the left ventricular transcriptome identified 1059 probe sets (adjusted P ≤ 0.05) differentially expressed between E2 (n = 5) and Ctrl (n = 5). Hypergeometric testing for Gene Ontology showed most genes to be associated with cell cycle, regulation of growth, cell and tissue development. Pathway analysis revealed 140 pathways (adjusted P = 0.05) modulated between the two groups, such as the DNA replication and Wnt signaling pathways. Next, we tested the hypothesis that this hypertrophic effect of E2 is of the physiological type. To this extent, we identified that angiogenesis was increased with cardiac growth as determined by the microarray analysis and VEGF-A protein levels assessed by Western blotting. Furthermore, the embryonic gene program was not activated and no fibrosis was observed in the E2-treated group. In conclusion, our study is the first to demonstrate pro-hypertrophic actions of E2 in the healthy heart through the modulation of growth-related genes and pathways. Due to that we have characterized the hypertrophic effect of E2 as physiological, we expect this effect to be beneficial for the heart.

Abstract 227: The Effect of PHLPP2 Removal on Cardiomyocyte Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Nicole H Purcell ◽  
Courtney Moc ◽  
Giovanni Birrueta ◽  
Amy Taylor ◽  
Walter Koch ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Preliminary Data ◽  
Nuclear Export ◽  
Nuclear Translocation ◽  
Cardiomyocyte Hypertrophy ◽  
Ph Domain ◽  
Akt Phosphorylation ◽  
Precise Control ◽  
Neonatal Cardiomyocytes ◽  
G Protein Coupled

Crucial cellular decisions that lead to cell growth, metabolism, proliferation, and survival are all dependent on the precise control of the phosphorylation state of proteins. The serine/threonine phosphatase, PHLPP (PH domain leucine-rich repeat protein phosphatase) has been shown to directly dephosphorylate several members of the AGC family of kinases. Knockdown of PHLPP1 by siRNA in neonatal cardiomyocytes potentiates Akt activity and phosphorylation specifically at Ser473 basally and following agonist stimulation while, the removal of PHLPP2 in cardiomyocytes does not affect Akt phosphorylation as previously reported in other cells. We hypothesize that PHLPP2 may target other AGC kinases in cardiomyocytes to regulate cardiac hypertrophy. Preliminary data suggests that removal of PHLPP2 activates fetal gene re-expression at baseline and potentiates phenylephrine (PE) induced gene expression 2 fold over siControl. Recently, G protein-coupled receptor kinase 5 (GRK5), which is an AGC kinase, has been shown to regulate cardiac hypertrophy through HDAC5 phosphorylation and de-repression of gene transcription. We wanted to determine whether PHLPP2 regulates GRK5 phosphorylation and localization in cardiomyocytes. GRK5 translocates to the nucleus following hypertrophic stimulation and we found that removal of PHLPP2 increased GRK5 translocation to the nucleus at baseline and with PE treatment compared to siControl cells. Also, removal of PHLPP2 increased nuclear export of HDAC5 at baseline and following PE treatment. Conversely, overexpression of PHLPP2 blocked nuclear translocation of GRK5 following PE treatment. Ongoing studies will determine whether PHLPP acts as a scaffold or if its phosphatase activity is necessary for inhibition of GRK5 translocation by directly measuring the phosphorylation of GRK5 in the presence and absence of PHLPP2 following hypertrophic stimulation. Our preliminary data is the first to uncover GRK5 as a novel PHLPP2 target in cardiomyocytes. Since little is known about the non-canonical regulation of GRK5, understanding whether phosphorylation and localization is regulated within the cardiomyocyte by PHLPP has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure.

Abstract 526: Unraveling the Molecular Signature of Pregnancy Induced Hypertrophy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Helen E Collins ◽  
Kyle Fulghum ◽  
Lindsey A McNally ◽  
Mallory L Foster ◽  
Kenneth Brittian ◽  
...  
Keyword(s):  
Late Pregnancy ◽  
Functional Adaptation ◽  
Molecular Signature ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Molecular Processes ◽  
Cross Sectional ◽  
Lv Mass ◽  
Lv Volume ◽  
Tibia Length

Cardiovascular disease is the leading cause of death in pregnant and postpartum women. During pregnancy, the maternal heart rapidly adapts to the increasing physiological and metabolic demands of the growing fetus. This adaptation often takes the form of a physiological hypertrophy in which the maternal heart grows to increase cardiac output; however, the molecular processes underlying pregnancy-induced hypertrophy (PIH) are poorly understood. The goal of this study was to examine the transcriptomic and metabolic signatures associated with the structural and functional adaptations of the heart to pregnancy. Therefore, we performed timed pregnancy studies in 12-week-old female FVB/NJ mice, which were distributed into the following groups: non-pregnant control (NP; n = 14), mid-pregnancy (MP, 6d pregnant; n = 11), late-pregnancy (LP, 16d pregnant; n = 13), and 1-wk post birth (PB; n = 8). Heart weight to tibia length were higher in MP (7.77±1.02 mg/mm; p <0.05), LP (7.84±0.87 mg/mm; p <0.05), and PB mice (9.86±1.14 mg/mm; p <0.05) compared with NP mice (6.54±0.74 mg/mm). The sustained increase in PB heart weight was associated with increased myocyte cross sectional area, consistent with cardiomyocyte hypertrophy. Compared with NP hearts, echocardiographic measurements suggest significant increases in both end diastolic (36.0±5.1 vs 61.2±5.9 μl; p <0.05) and systolic LV volume (9.4±3.8 vs 21.0±1.4 μl; p <0.05) in PB hearts. These changes in PB hearts were associated with a significant increase in LV mass and a decline in ejection fraction. In LP and PB hearts, we also found higher expression of markers of hypertrophy ( Nppa, Nppb, Myh7 ). Subsequent RNA-seq analyses revealed enrichment in genes involved in cell proliferation, cytokinesis, and transcription in MP hearts; in metabolism genes in LP hearts; and in fibrotic and extracellular matrix genes in PB hearts. Together, these findings reveal the key molecular signature underlying the structural and functional adaptation of the heart during pregnancy and parturition, and may shed light on the molecular processes underlying PIH.

scholarly journals Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

2015 ◽  
Vol 36 (4) ◽  
pp. 1597-1612 ◽  
Author(s):  
Lei Liu ◽  
Chao Wang ◽  
Dianjun Sun ◽  
Shuangquan Jiang ◽  
Hong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Ang Ii

Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

scholarly journals Elevated myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

2010 ◽  
Vol 42 (3) ◽  
pp. 374-383 ◽  
Author(s):  
Jin Xue ◽  
Fatima Mraiche ◽  
Dan Zhou ◽  
Morris Karmazyn ◽  
Tatsujiro Oka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Gene Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Cross Sectional

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

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