scholarly journals Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriel Komla Adzika ◽  
Hongjian Hou ◽  
Adebayo Oluwafemi Adekunle ◽  
Ruqayya Rizvi ◽  
Seyram Yao Adzraku ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Troponin I ◽  
Inflammatory Responses ◽  
Myocardial Hypertrophy ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Myocardial Inflammation ◽  
Treatment Interventions ◽  
Pathological Cardiac Hypertrophy

Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy—pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 μM/ml) and/or Forskolin (10 μM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.

scholarly journals IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

2015 ◽  
Vol 308 (7) ◽  
pp. R627-R635 ◽  
Author(s):  
Kimberley C. W. Wang ◽  
Darran N. Tosh ◽  
Song Zhang ◽  
I. Caroline McMillen ◽  
Jaime A. Duffield ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Cardiac Hypertrophy ◽  
Histone Acetylation ◽  
Troponin I ◽  
Adult Life ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Average Birth Weight ◽  
Increased Risk

The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.

Abstract 119: Targeting Cardiac Hypertrophy with Small Molecule Inhibitors of JMJD2A

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Qing-jun Zhang ◽  
Ganesha Rai ◽  
Ajit Jadhav ◽  
Anton Simeonov ◽  
David Maloney ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Enzymatic Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Epigenetic Modification ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Innovative Drug ◽  
Pathological Cardiac Hypertrophy

One of the major challenges in managing and treating heart failure patients is to develop disease-modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes remodeling processes, including left ventricular hypertrophy and reprogramming of gene expression. Understanding the mechanisms involved could provide a key to develop interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, regulates gene transcription in response to environmental signals. JMJD2A is a trimethyl-lysine specific histone lysine demethylase. To study the role of JMJD2A, we generated heart specific JMJD2A overexpression and deletion mouse lines. Our studies with these genetically modified mice indicated that JMJD2A is required for pathological cardiac hypertrophy. Furthermore, we show that the demethylase activity of JMJD2A is required for its transcriptional activity. These data suggests that targeting JMJD2A enzymatic activity may be used to suppress hypertrophic remodeling. To test this hypothesis, we tested a collection of small molecule inhibitors of JMJD2 in collaboration with Chemists in NIH and identified several small molecule inhibitors of JMJD2A that are active in cell-based assays. These small molecule inhibitors of JMJD2A inhibited the phenylephrine-stimulated cardiomyocyte hypertrophy in vitro. Our data suggests that JMJD2A enzymatic activity may act as a hypertrophic determinant and may be an innovative drug target for prevention and treatment of pathological cardiac hypertrophy and heart failure.

scholarly journals Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Bing Zhang ◽  
Yanzhen Tan ◽  
Zhengbin Zhang ◽  
Pan Feng ◽  
Wenyuan Ding ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Test Group ◽  
Neonatal Rat ◽  
Activation Mechanism ◽  
Cardiomyocyte Hypertrophy ◽  
Control Group ◽  
Pathological Cardiac Hypertrophy

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway

2019 ◽  
Vol 116 (1) ◽  
pp. 114-126 ◽  
Author(s):  
Xiaoying Yan ◽  
Ran Zhao ◽  
Xiaorong Feng ◽  
Jingzhou Mu ◽  
Ying Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Transforming Growth Factor ◽  
Troponin T ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii

Abstract Aims Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. Methods and results Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt −1285 to −1274 bp) in the cardiomyocytes following ANG II stimulus. Conclusion Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.

scholarly journals AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Anca Remes ◽  
Andreas H. Wagner ◽  
Nesrin Schmiedel ◽  
Markus Heckmann ◽  
Theresa Ruf ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Myocardial Hypertrophy ◽  
Cardiomyocyte Hypertrophy ◽  
Activated T Cells ◽  
Specific Expression ◽  
Adult Mice ◽  
Before And After ◽  
A Cell

AbstractPrevious studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

scholarly journals LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shi Peng ◽  
Xiao-feng Lu ◽  
Yi-ding Qi ◽  
Jing Li ◽  
Juan Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Aims. We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. Methods. In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. Results. Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. Conclusions. LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

Abstract 87: Endothelial Nogo-B Regulates Sphingolipid Biosynthesis to Promote the Onset of Pathological Hypertrophy During Chronic Pressure Overload

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yi Zhang ◽  
Yan Huang ◽  
Anna Cantalupo ◽  
Paula S Azevedo ◽  
Mauro Siragusa ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
De Novo ◽  
Heart Function ◽  
Critical Role ◽  
Pressure Overload ◽  
Myocardial Inflammation ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Sphingolipid Biosynthesis

Chronic pressure overload leads to an initial compensatory cardiac hypertrophy, and eventually to heart failure. The mechanisms regulating the transition from adaptive to pathological cardiac hypertrophy remain elusive. We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular functions by inhibiting the rate-limiting enzyme in de novo sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Here, we show that sphingolipids produced by the vasculature, particularly S1P, protect the heart function during pressure overload, through a paracrine mode of action. SPT activity is upregulated in banded hearts in vivo , as well as in TNF-α-activated endothelium in vitro , and loss of Nogo-mediated brake on SPT increases the production of S1P, which enhances the coronary vasculature compliance to high pressure and endothelial barrier. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B-deficient mice to wild-type levels; whereas SEW2871, an S1P 1 receptor agonist, prevents myocardial inflammation and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy, and proposes a potential new therapeutic target for the attenuation or reversal of this clinical condition.

scholarly journals The proarrhythmic features of pathological cardiac hypertrophy in neonatal rat ventricular cardiomyocyte cultures

2020 ◽  
Vol 128 (3) ◽  
pp. 545-553
Author(s):  
Zeinab Neshati ◽  
Martin J. Schalij ◽  
Antoine A. F. de Vries
Keyword(s):  
Action Potential ◽  
Cardiac Hypertrophy ◽  
Action Potential Duration ◽  
In Vitro Model ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Control Group ◽  
Pathological Cardiac Hypertrophy ◽  
Vitro Model

Different factors may trigger arrhythmias in diseased hearts, including fibrosis, cardiomyocyte hypertrophy, hypoxia, and inflammation. This makes it difficult to establish the relative contribution of each of them to the occurrence of arrhythmias. Accordingly, in this study, we used an in vitro model of pathological cardiac hypertrophy (PCH) to investigate its proarrhythmic features and the underlying mechanisms independent of fibrosis or other PCH-related processes. Neonatal rat ventricular cardiomyocyte (nr-vCMC) monolayers were treated with phorbol 12-myristate 13-acetate (PMA) to create an in vitro model of PCH. The electrophysiological properties of PMA-treated and control monolayers were analyzed by optical mapping at day 9 of culture. PMA treatment led to a significant increase in cell size and total protein content. It also caused a reduction in sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 level (32%) and an increase in natriuretic peptide A (42%) and α1-skeletal muscle actin (34%) levels, indicating that the hypertrophic response induced by PMA was, indeed, pathological in nature. PMA-treated monolayers showed increases in action potential duration (APD) and APD dispersion, and a decrease in conduction velocity (CV; APD30 of 306 ± 39 vs. 148 ± 18 ms, APD30 dispersion of 85 ± 19 vs. 22 ± 7 and CV of 10 ± 4 vs. 21 ± 2 cm/s in controls). Upon local 1-Hz stimulation, 53.6% of the PMA-treated cultures showed focal tachyarrhythmias based on triggered activity ( n = 82), while the control group showed 4.3% tachyarrhythmias ( n = 70). PMA-treated nr-vCMC cultures may, thus, represent a well-controllable in vitro model for testing new therapeutic interventions targeting specific aspects of hypertrophy-associated arrhythmias. NEW & NOTEWORTHY Phorbol 12-myristate 13-acetate (PMA) treatment of neonatal rat ventricular cardiomyocytes (nr-vCMCs) led to induction of many significant features of pathological cardiac hypertrophy (PCH), including action potential duration prolongation and dispersion, which provided enough time and depolarizing force for formation of early afterdepolarization (EAD)-induced focal tachyarrhythmias. PMA-treated nr-vCMCs represent a well-controllable in vitro model, which mostly resembles to moderate left ventricular hypertrophy (LVH) rather than severe LVH, in which generation of a reentry is the putative mechanism of its arrhythmias.

FNDC5/Irisin inhibits pathological cardiac hypertrophy

2019 ◽  
Vol 133 (5) ◽  
pp. 611-627 ◽  
Author(s):  
Qing Yu ◽  
Wenxin Kou ◽  
Xu Xu ◽  
Shunping Zhou ◽  
Peipei Luan ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Pressure Overload ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Pathological Cardiac Hypertrophy ◽  
Adam Family ◽  
A Disintegrin And Metalloproteinase

Abstract Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro. Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.

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.

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