Abstract 169: Elucidating the role of GRK5 in Physiological Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Alessandro Cannavo ◽  
Jonathan Hullmann ◽  
Jessica L Gold ◽  
Walter J Koch
Keyword(s):  
Exercise Training ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Hypertrophic Response ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Hypertrophy

Cardiac function is dynamically regulated by various G protein-coupled receptors (GPCRs). GPCR kinases (GRKs) are important in cardiac GPCR regulation through phosphorylation and desensitization of these receptors. GRK2 and GRK5 are the predominant GRKs in the heart, and the most widely characterized as they are both up-regulated in the failing heart. Prior studies from our Lab have determined that GRK5 plays a crucial role in pathological cardiac hypertrophy. Another type of hypertrophy termed, “physiological hypertrophy” occurs with exercise training and is defined as an enlargement in cardiac myocyte size leading to favorable cardiac adaptations. At present, it is unclear if GRK5 is a regulator of physiological hypertrophy in addition to its role in maladaptive hypertrophy. We hypothesize that GRK5 will not regulate physiological hypertrophy such that mice with cardiac-specific overexpression of GRK5 (TgGRK5) will yield a similar post-exercise cardiac physiological hypertrophic response as that of control wild-type (WT) mice. To test this hypothesis, TgGRK5 and WT mice were exposed to a 21 day high-intensity swimming exercise protocol. For each line, sham mice, which did not swim served as appropriate controls. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured. TgGRK5 and WT mice both exhibited a characteristic 10-15% increase in HW/BW and HW/TL ratios, which are standard measures of cardiac hypertrophy. In addition, hearts were sectioned and H&E stained to evaluate myocyte size. Both TgGRK5 and WT mice exhibited a significant increase in myocyte size. Cardiac function was evaluated via echocardiography both prior to and after exercise training, and no changes were observed between TgGRK5 and WT mice after training. These data were re-affirmed in H9C2 cells and neonatal rat ventricular myocytes overexpressing either GFP or GRK5, which exhibited similar increases in cell size and AKT phosphorylation after IGF-1 treatment, a physiological hypertrophy stimulus. Taken together, these data suggest that physiological hypertrophy is similar in both control and TgGRK5 mice, confirming that GRK5 is solely a regulator of pathological cardiac hypertrophy.

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

2018 ◽  
Vol 115 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Andrea Grund ◽  
Malgorzata Szaroszyk ◽  
Janina K Döppner ◽  
Mona Malek Mohammadi ◽  
Badder Kattih ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Binding Protein ◽  
Treatment Strategies ◽  
Pressure Overload ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.

Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo

1996 ◽  
Vol 271 (6) ◽  
pp. H2197-H2208 ◽  
Author(s):  
J. Lai ◽  
H. Jin ◽  
R. Yang ◽  
J. Winer ◽  
W. Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Chronic Administration ◽  
Heart Weight ◽  
Adult Rats ◽  
Myocyte Hypertrophy ◽  
Cardiac Myocyte Hypertrophy

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.

Abstract 265: CITED4 Induces Physiologic Hypertrophy and Improves Cardiac Remodeling After Ischemic Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Vassilios J Bezzerides ◽  
Colin Platt ◽  
Kaavya Paruchuri ◽  
Loren Oh ◽  
Chunyang Xiao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Gene Profiling ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Autophagic Flux

Cardiac hypertrophy is an adaptive response to increased hemodynamic stresses, which can be either physiologic, as with exercise, or pathologic, as with valvular heart disease. Recent data suggest that physiologic hypertrophy secondary to exercise may be mediated by the transcription factor CEBPβ and the p300-interacting protein CITED4. We sought to investigate the cardiovascular effects of CITED4 expression in vivo. Using a cardiac-specific and inducible transgenic mouse (Tg) model, we determined the effects of CITED4 expression on cardiac parameters including heart weight, cell size, cardiac function and gene expression. Expression of CITED4 for 3 weeks induced increases in heart weight (22% in HW/TL, p < 0.01) and cardiomyocyte (CM) size (24.5% in cell area, p < 0.001) with normal systolic function and without evidence of fibrosis. Gene profiling demonstrated increased expression of cardiac troponin, a favorable αMHC/βMHC ratio and a reduction in BNP consistent with physiologic hypertrophy. Genome-wide expression profiling of neonatal rat ventricular myocytes (NRVMs) over-expressing CITED4 demonstrated the activation of a unique set of genes including BCL2, ATP12a, Efemp1, Ifi204 and Tcf19. To further examine the potential beneficial role of CITED4, we induced ischemia by transient occlusion of the left anterior descending (LAD) coronary (30 min) followed by reperfusion for 24 hours, 6 days or 4 weeks. At 24 hrs after ischemia-reperfusion injury (IRI), neither cardiac dysfunction on echo nor infarct sizes were different between CITED4 Tg and controls. However, CITED4 Tgs showed substantial recovery of cardiac function at 4 weeks (FS: CITED4 Tg 51%, Control 34%, p < 0.01) and a 3.4-fold reduction in fibrosis (p < 0.005). Analysis of possible cellular responses responsible for the functional recovery demonstrated enhanced autophagic flux with reduced accumulation of LC3II (down 71%, p<0.05) and p62 (down 54%, p<0.005). Further examination of the involved signaling pathway revealed direct activation of mTORC1 and its effectors consistent with a growth phenotype. We conclude that CITED4 expression is sufficient to induce physiologic cardiac hypertrophy and improves cardiac remodeling after ischemic injury likely through activation of mTORC1.

Abstract 434: Sirt4 Accelerates Ang II-induced Pathological Cardiac Hypertrophy by Inhibiting Mnsod Activity

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Depei Liu ◽  
Yu-Xuan Luo ◽  
Xiaoqiang Tang ◽  
Xi-Zhou An ◽  
Xue-Min Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Manganese Superoxide Dismutase ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. Methods and results: Male C57BL/6 Sirt4 knockout mice, transgenic mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analyzed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-transgenic mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with MnTBAP, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. Conclusions: Sirt4 promotes hypertrophic growth and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

2006 ◽  
Vol 290 (3) ◽  
pp. H985-H994 ◽  
Author(s):  
Tuanzhu Ha ◽  
Fang Hua ◽  
Yuehua Li ◽  
Jing Ma ◽  
Xiang Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Aortic Banding ◽  
Myocyte Apoptosis ◽  
Cardiac Myocyte Apoptosis

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts ( n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats ( n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation ( n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 ± 0.013 vs. 0.31 ± 0.008), HW/TL by 47.2% (42.7 ± 1.30 vs. 29.0 ± 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 ± 0.006 vs. 0.44 ± 0.013) and HW/TL by 22.3% (33.2 ± 0.95 vs. 42.7 ± 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-κB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.

scholarly journals Divergent and Overlapping Roles for Selected Phytochemicals in the Regulation of Pathological Cardiac Hypertrophy

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1210
Author(s):  
Levi Evans ◽  
Yiqui Shen ◽  
Abigail Bender ◽  
Leah E. Burnett ◽  
Musheng Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Ventricular Myocytes ◽  
Neonatal Rat ◽  
Berberine Hydrochloride ◽  
Clinical Endpoints ◽  
Pathological Cardiac Hypertrophy ◽  
Divergent Gene ◽  
New Findings ◽  
Mitogen Activated Protein

Plant-based foods, like fruits, vegetables, whole grains, legumes, nuts, seeds and other foodstuffs, have been deemed as heart healthy. The chemicals within these plant-based foods, i.e., phytochemicals, are credited with protecting the heart. However, the mechanistic actions of phytochemicals, which prevent clinical endpoints, such as pathological cardiac hypertrophy, are still being elucidated. We sought to characterize the overlapping and divergent mechanisms by which 18 selected phytochemicals prevent phenylephrine- and phorbol 12-myristate 13-acetate-mediated cardiomyocyte enlargement. Of the tested 18 compounds, six attenuated PE- and PMA-mediated enlargement of neonatal rat ventricular myocytes. Cell viability assays showed that apigenin, baicalein, berberine hydrochloride, emodin, luteolin and quercetin dihydrate did not reduce cell size through cytotoxicity. Four of the six phytochemicals, apigenin, baicalein, berberine hydrochloride and emodin, robustly inhibited stress-induced hypertrophy and were analyzed further against intracellular signaling and genome-wide changes in mRNA expression. The four phytochemicals differentially regulated mitogen-activated protein kinases and protein kinase D. RNA-sequencing further showed divergence in gene regulation, while pathway analysis demonstrated overlap in the regulation of inflammatory pathways. Combined, this study provided a comprehensive analysis of cardioprotective phytochemicals. These data highlight two defining observations: (1) that these compounds predominantly target divergent gene pathways within cardiac myocytes and (2) that regulation of overlapping signaling and gene pathways may be of particular importance for the anti-hypertrophic actions of these phytochemicals. Despite these new findings, future works investigating rodent models of heart failure are still needed to understand the roles for these compounds in the heart.

Expression of an active LKB1 complex in cardiac myocytes results in decreased protein synthesis associated with phenylephrine-induced hypertrophy

2007 ◽  
Vol 292 (3) ◽  
pp. H1460-H1469 ◽  
Author(s):  
Anna A. Noga ◽  
Carrie-Lynn M. Soltys ◽  
Amy J. Barr ◽  
Suzanne Kovacic ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Adaptor Protein ◽  
Neonatal Rat ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy ◽  
Neonatal Rat Cardiac Myocytes ◽  
Rat Cardiac Myocytes

AMP-activated protein kinase (AMPK) is a major metabolic regulator in the cardiac myocyte. Recently, LKB1 was identified as a kinase that regulates AMPK. Using immunoblot analysis, we confirmed high expression of LKB1 in isolated rat cardiac myocytes but show that, under basal conditions, LKB1 is primarily localized to the nucleus, where it is inactive. We examined the role of LKB1 in cardiac myocytes, using adenoviruses that express LKB1, and its binding partners Ste20-related adaptor protein (STRADα) and MO25α. Infection of neonatal rat cardiac myocytes with all three adenoviruses substantially increased LKB1/STRADα/MO25α expression, LKB1 activity, and AMPKα phosphorylation at its activating phosphorylation site (threonine-172). Since activation of AMPK can inhibit hypertrophic growth and since LKB1 is upstream of AMPK, we hypothesized that expression of an active LKB1 complex would also inhibit protein synthesis associated with hypertrophic growth. Expression of the LKB1/STRADα/MO25α complex in neonatal rat cardiac myocytes inhibited the increase in protein synthesis observed in cells treated with phenylephrine (measured via [3H]phenylalanine incorporation). This was associated with a decreased phosphorylation of p70S6 kinase and its substrate S6 ribosomal protein, key regulators of protein synthesis. In addition, we show that the pathological cardiac hypertrophy in transgenic mice with cardiac-specific expression of activated calcineurin is associated with a significant decrease in LKB1 expression. Together, our data show that increased LKB1 activity in the cardiac myocyte can decrease hypertrophy-induced protein synthesis and suggest that LKB1 activation may be a method for the prevention of pathological cardiac hypertrophy.

P1606Glutamine-fructose-6-phosphate amidotransferase 2 mediates isoproterenol-induced cardiac hypertrophy by increasing Akt O-GlcNAcylation through hexosamine biosynthesis pathway

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Ishikita ◽  
S Matsushima ◽  
S Ikeda ◽  
K Okabe ◽  
T Tadokoro ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Biosynthesis Pathway ◽  
Post Translational Modification ◽  
Expression Levels ◽  
Pathological Cardiac Hypertrophy ◽  
Hexosamine Biosynthesis ◽  
Hexosamine Biosynthesis Pathway

Abstract Background Cardiac hypertrophy is an independent risk factor for heart failure and cardiac death. Hexosamine biosynthesis pathway (HBP), an accessory pathways of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. However, the role of HBP has not been determined in pathological cardiac hypertrophy. Purpose The purpose of this study to examine whether glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical enzyme of HBP, mediates cardiac hypertrophy by protein O-GlcNAcylation and activating hypertrophic signaling in cardiomyocytes. Methods and results C57BL/6J mice were treated with isoproterenol (ISO: 15 mg/kg/day, 1 week) with or without 6-Diazo-5-oxo-L-norleucine (DON, an inhibitor of GFAT: 500 μg/kg/day, 1week). ISO-treated mice (ISO+vehicle) showed cardiac hypertrophy, which were attenuated in ISO and DON-treated mice (ISO+DON) (heart weight to tibial length ratio: 7.70±0.09 vs. 7.11±0.15 mg/mm, n=12, p<0.05, left ventricular wall thickness: 1.05±0.02 vs. 0.86±0.03 mm, n=6, p<0.05). Cardiomyocyte cross-sectional area was also decreased in ISO+DON compared with ISO+vehicle (309±25 vs. 252±13 mm2, n=,3 p<0.05). Whereas expression levels of GFAT2 and protein O-GlcNAcylation in the heart were increased in ISO+vehicle compared with control+vehicle by 3.3 and 1.5 folds, respectively (n=9 and n=9, p<0.05), expression levels of O-GlcNAc transferase (OGT) and the β-N-acetylglucosaminidase (OGA), other enzymes regulating O-GlcNAcylation, were not altered in both groups, indicating that ISO activated HBP by GFAT2. Protein O-GlcNAcylation in ISO+DON was lower than that in ISO+vehicle by 83% (n=9, p<0.05). In addition, phosphorylation of Akt, a critical mediator of cardiac hypertrophy, but not other mediators of cardiac hypertrophy such as ERK, JNK, or p38MAPK, was significantly decreased in ISO+DON by 76% (n=9, p<0.05). In cultured neonatal rat ventricular myocytes, treatment with ISO (1μM, 12h) increased the expression levels of GFAT2 and protein O-GlcNAcylation by 1.3 and 1.5 folds, respectively (n=6 and n=6, p<0.05), but not GFAT1. Furthermore, ISO stimulation increased a direct O-GlcNAcylation of Akt by 1.4 folds (n=3, p<0.05). Downregulation of GFAT2 by RNA silencing decreased cell size by 82% (n=6, p<0.05) and protein O-GlcNAcylation and phosphorylation of Akt by 76% and 54%, respectively (n=9 and n=9, p<0.05) in cardiomyocyte treated with ISO. Conversely, administration of glucosamine, a substrate of HBP, increased protein of O-GlcNAcylation and phosphorylation of Akt by 1.3 and 1.8 folds, respectively (n=6 and n=6, p<0.05). Conclusions GFAT2, a limiting enzyme of HBP, mediates pathological cardiac hypertrophy by Akt activation probably due to its O-GlcNAcylation. GFAT2-O-GlcNAcylation-Akt pathway might be a potential novel therapeutic target for cardiac hypertrophy.

scholarly journals Lysosomal-Associated Protein Transmembrane 5 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

2021 ◽  
Vol 8 ◽  
Author(s):  
Lu Gao ◽  
Sen Guo ◽  
Rui Long ◽  
Lili Xiao ◽  
Rui Yao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Therapeutic Potential ◽  
Negative Regulator ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy

Lysosomal-associated protein transmembrane 5 (LAPTM5) is mainly expressed in immune cells and has been reported to regulate inflammation, apoptosis and autophagy. Although LAPTM5 is expressed in the heart, whether LAPTM5 plays a role in regulating cardiac function remains unknown. Here, we show that the expression of LAPTM5 is dramatically decreased in murine hypertrophic hearts and isolated hypertrophic cardiomyocytes. In this study, we investigated the role of LAPTM5 in pathological cardiac hypertrophy and its possible mechanism. Our results show that LAPTM5 gene deletion significantly exacerbates cardiac remodeling, which can be demonstrated by reduced myocardial hypertrophy, fibrosis, ventricular dilation and preserved ejection function, whereas the opposite phenotype was observed in LAPTM5 overexpression mice. In line with the in vivo results, knockdown of LAPTM5 exaggerated angiotensin II-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes, whereas overexpression of LAPTM5 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, LAPTM5 directly bound to Rac1 and further inhibited MEK-ERK1/2 signaling, which ultimately regulated the development of cardiac hypertrophy. In addition, the antihypertrophic effect of LAPTM5 was largely blocked by constitutively active mutant Rac1 (G12V). In conclusion, our results suggest that LAPTM5 is involved in pathological cardiac hypertrophy and that targeting LAPTM5 has great therapeutic potential in the treatment of pathological cardiac hypertrophy.

Abstract 157: Alterations in Signaling Pathways During Regression of Pathological Cardiac Hypertrophy

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Deanna Langager ◽  
Leslie Leinwand
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathways ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Akt Pathway ◽  
Compensatory Mechanism ◽  
Akt Inhibitor ◽  
Pathological Cardiac Hypertrophy

Introduction: Cardiac hypertrophy is initially, a compensatory mechanism to maintain cardiac output when there is an increased load on the heart. However, if cardiac hypertrophy persists for an extended time, there can be maladaptive changes to the myocardium. Even when the underlying cause of hypertrophy is treated, regression is often minimal or absent. Clinical cases of cardiac regression do exist, including patients receiving bariatric surgery or a left ventricular assist device. While many of the mechanisms leading to cardiac hypertrophy are well understood, little is known about the mechanisms of reversal of hypertrophy and why it is sometimes irreversible. We hypothesized that a reversal of isoproterenol (Iso) induced cardiac hypertrophy in the mouse will be observed within 7 days following the removal of the stimulus and we will be able to identify alterations in signaling pathways. Methods: We induced pathological cardiac hypertrophy with Iso for 7 days, at which peak hypertrophy is achieved. To identify if/when regression occurs, the Iso treatment was stopped and the mice were monitored for 7 days. Heart weights were measured at peak hypertrophy, post-drug days 1, 2, 3 & 7, along with vehicle treated mice (8/group). We used left ventricle tissue for protein analysis and protein degradation activity assays. Results: Regression from cardiac hypertrophy occurs by post-drug day 7 (p=0.016) in the Iso mouse model. p-Akt is increased with Iso treatment and returns to vehicle control levels by post-drug day 7. There is a decrease in p-mTOR and an increase in LC3-II levels at post-drug day 7, indicating a possible role of autophagy in cardiac regression. In addition, there was a decrease in cell size when neonatal rat ventricular myocytes were treated with the Akt inhibitor, Wortmannin, following phenylephrine induced hypertrophy. Conclusion: Regression of Iso-induced cardiac hypertrophy occurs in the mouse after 7 days following the removal of the stimulus. The Akt pathway is activated with Iso treatment and when this pathway is inactivated during regression, autophagy is activated, which may be an important mechanism to degrade proteins and lead to a decrease in cardiac hypertrophy. Finally, when the Akt pathway is inhibited in vitro , hypertrophic cells regress.

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