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

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.

Download Full-text

Abstract 169: Elucidating the role of GRK5 in Physiological Hypertrophy

Circulation Research ◽

10.1161/res.115.suppl_1.169 ◽

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.

Download Full-text

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

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.740526 ◽

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.

Download Full-text

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

Circulation Research ◽

10.1161/res.121.suppl_1.157 ◽

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.

Download Full-text

Bakuchiol protects against pathological cardiac hypertrophy by blocking NF-κB signaling pathway

Bioscience Reports ◽

10.1042/bsr20181043 ◽

2018 ◽

Vol 38 (5) ◽

Cited By ~ 2

Author(s):

Zheng Wang ◽

Lu Gao ◽

Lili Xiao ◽

Lingyao Kong ◽

Huiting Shi ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Pressure Overload ◽

Neonatal Rat ◽

Oral Gavage ◽

Aortic Banding ◽

Rat Cardiomyocytes ◽

Pathological Cardiac Hypertrophy ◽

First Time

Bakuchiol (Bak), a monoterpene phenol isolated from the seeds of Psoralea corylifolia, has been widely used to treat a large variety of diseases in both Indian and Chinese folkloric medicine. However, the effects of Bak on cardiac hypertrophy remain unclear. Therefore, the present study was designed to determine whether Bak could alleviate cardiac hypertrophy. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy model. Bak of 1 ml/100 g body weight was given by oral gavage once a day from 1 to 8 weeks after surgery. Our data demonstrated for the first time that Bak could attenuate pressure overload-induced cardiac hypertrophy and could attenuate fibrosis and the inflammatory response induced by AB. The results further revealed that the effect of Bak on cardiac hypertrophy was mediated by blocking the activation of the NF-κB signaling pathway. In vitro studies performed in neonatal rat cardiomyocytes further proved that the protective effect of Bak on cardiac hypertrophy is largely dependent on the NF-κB pathway. Based on our results, Bak shows profound potential for its application in the treatment of pathological cardiac hypertrophy, and we believe that Bak may be a promising therapeutic candidate to treat cardiac hypertrophy and heart failure.

Download Full-text

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

Cardiovascular Research ◽

10.1093/cvr/cvy154 ◽

2018 ◽

Vol 115 (1) ◽

pp. 71-82 ◽

Cited By ~ 5

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.

Download Full-text

Emodin Attenuates Pathological Cardiac Hypertrophy by Regulating Gene Expression Through Acetyl-histone-mediated Actions (P06-036-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-036-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Levi Evans ◽

Bradley Ferguson

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Histone Acetylation ◽

Regulation Of Gene Expression ◽

Epigenetic Modifications ◽

Neonatal Rat ◽

Heart Health ◽

Hdac Activity ◽

Pathological Cardiac Hypertrophy ◽

Epigenetic Regulators

Abstract Objectives Epigenetic modifications regulate gene expression without changing DNA sequence and are reversible, highlighting their therapeutic potential for heart failure. Recent evidence suggests that food compounds can reverse these stress-induced epigenetic modifications, yet few studies have characterized their role as epigenetic regulators of heart health. Our objective tested the hypothesis that Emodin, an Antraquinone found in rhubarb, blocked pathological cardiac hypertrophy via acetyl-histone-mediated gene expression changes. Methods To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were stimulated with phenylephrine (PE, 10 μM) to induce receptor-mediated pathological cardiac hypertrophy in the absence or presence of vehicle control or Emodin (10 μM) for 48 hours. Cells were subsequently 1) fixed for immunostaining and cell size quantification, 2) lysed for protein to assess HDAC activity and histone acetylation or 3) lysed for RNA to analyze transcriptome–wide changes in gene expression. A minimum of three experiments with an n = 3/group was performed and data quantified. One-way ANOVA with Tukey's post-hoc was performed unless otherwise specified. p < 0.05 was considered significant. Results Emodin significantly blocked PE-induced hypertrophy. Emodin significantly inhibited HDAC activity concomitant to increased histone acetylation. Lastly, Emodin reversed stress-induced changes in gene expression. Conclusions Our data suggest that Emodin inhibited pathological cardiac hypertrophy via acetyl-histone dependent regulation of gene expression. While animal studies are currently underway to examine the epigenetic actions for emodin in cardiac protection, our results support the role for food compounds like Emodin as epigenetic regulators of heart health. Funding Sources This work is supported by the USDA NIFA (Hatch-NEV00727), the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research and by the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459) to B.S.F. Core facilities used for Research were supported by NIGMS of the NIH (P20 GM103554).

Download Full-text

Carbonic anhydrase II promotes cardiomyocyte hypertrophy

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-142 ◽

2012 ◽

Vol 90 (12) ◽

pp. 1599-1610 ◽

Cited By ~ 24

Author(s):

Brittany F. Brown ◽

Anita Quon ◽

Jason R.B. Dyck ◽

Joseph R. Casey

Keyword(s):

Carbonic Anhydrase ◽

Ventricular Myocytes ◽

Dominant Negative ◽

Neonatal Rat ◽

Carbonic Anhydrase Ii ◽

Cardiomyocyte Hypertrophy ◽

Wild Type ◽

Over Expression ◽

Pathological Cardiac Hypertrophy ◽

Neonatal Rat Ventricular Myocytes

Pathological cardiac hypertrophy, the maladaptive remodelling of the myocardium, often progresses to heart failure. The sodium–proton exchanger (NHE1) and chloride–bicarbonate exchanger (AE3) have been implicated as important in the hypertrophic cascade. Carbonic anhydrase II (CAII) provides substrates for these transporters (protons and bicarbonate, respectively). CAII physically interacts with NHE1 and AE3, enhancing their respective ion transport activities by increasing the concentration of substrate at their transport sites. Earlier studies found that a broad-spectrum carbonic anhydrase inhibitor prevented cardiomyocyte hypertrophy (CH), suggesting that carbonic anhydrase is important in the development of hypertrophy. Here we investigated whether cytosolic CAII was the CA isoform involved in hypertrophy. Neonatal rat ventricular myocytes (NRVMs) were transduced with recombinant adenoviral constructs to over-express wild-type or catalytically inactive CAII (CAII-V143Y). Over-expression of wild-type CAII in NRVMs did not affect CH development. In contrast, CAII-V143Y over-expression suppressed the response to hypertrophic stimuli, suggesting that CAII-V143Y behaves in a dominant negative fashion over endogenous CAII to suppress hypertrophy. We also examined CAII-deficient (Car2) mice, whose hearts exhibit physiological hypertrophy without any decrease in cardiac function. Moreover, cardiomyocytes from Car2 mice do not respond to prohypertrophic stimulation. Together, these findings support a role of CAII in promoting CH.

Download Full-text

Sophoricoside ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy

Bioscience Reports ◽

10.1042/bsr20200661 ◽

2020 ◽

Vol 40 (11) ◽

Author(s):

Maomao Gao ◽

Fengjiao Hu ◽

Manli Hu ◽

Yufeng Hu ◽

Hongjie Shi ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Dependent Manner ◽

Protective Effects ◽

Rat Cardiomyocytes ◽

Pathological Cardiac Hypertrophy ◽

Compound C

Abstract Aim: The study aims to evaluate protective effects of sophoricoside (Sop) on cardiac hypertrophy. Meanwhile, the potential and significance of Sop should be broadened and it should be considered as an attractive drug for the treatment of pathological cardiac hypertrophy and heart failure. Methods: Using the phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) enlargement model, the potent protection of Sop against cardiomyocytes enlargement was evaluated. The function of Sop was validated in mice received transverse aortic coarctation (TAC) or sham surgery. At 1 week after TAC surgery, mice were treated with Sop for the following 4 weeks, the hearts were harvested after echocardiography examination. Results: Our study revealed that Sop significantly mitigated TAC-induced heart dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, Sop treatment induced a remarkable activation of AMPK/mTORC1-autophagy cascade following sustained hypertrophic stimulation. Importantly, the protective effect of Sop was largely abolished by the AMPKα inhibitor Compound C, suggesting an AMPK activation-dependent manner of Sop function on suppressing pathological cardiac hypertrophy. Conclusion: Sop ameliorates cardiac hypertrophy by activating AMPK/mTORC1-mediated autophagy. Hence, Sop might be an attractive candidate for the treatment of pathological cardiac hypertrophy and heart failure.

Download Full-text

Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6304058 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Hai-han Liao ◽

Nan Zhang ◽

Yan-yan Meng ◽

Hong Feng ◽

Jing-jing Yang ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Mapk Signaling ◽

Neonatal Rat ◽

Mouse Heart ◽

Pathological Cardiac Hypertrophy ◽

Pathological Hypertrophy ◽

Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

Download Full-text