scholarly journals Pressure Overload–Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1559-1570
Author(s):  
Ferda Demir ◽  
Kyoji Urayama ◽  
Anais Audebrand ◽  
Ayca Toprak-Semiz ◽  
Marja Steenman ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Conditioned Medium ◽  
Prolonged Exposure ◽  
Pressure Overload ◽  
Activin A ◽  
Autocrine Signaling ◽  
Hypertrophic Growth ◽  
Prokineticin 2 ◽  
Pathway Gene ◽  
Transaortic Constriction

Chronic cardiac pressure overload, caused by conditions, such as hypertension, induces pathological hypertrophic growth of myocardium and vascular rarefaction, with largely unknown mechanisms. Here, we described that expression of the PKR2 (prokineticin-2 receptor) is increased in the cardiomyocytes of mice following transaortic constriction pressure overload–mediated pathological hypertrophy. To identify PKR2-induced pathways, we performed microarray analysis on TG-PKR2 (transgenic mice overexpressing cardiomyocyte-restricted human PKR2) hearts and cytokine analyses in hPKR2 overexpressing H9c2-lines (PKR2-cardiomyocytes). An enrichment of activin pathway gene sets was found in both TG-PKR2 and transaortic constriction-operated hearts. Elevated levels of 2 cytokines activin A and its coreceptor, sENG (soluble Endoglin), were found in both PKR2-cardiomyocytes and in PKR2-cardiomyocytes conditioned medium. ELISA analyses of the cardiomyocytes derived from both TG-PKR2 and transaortic constriction hearts revealed high levels of these cardiokines that were repressed with antibodies blocking PKR2, indicating a PKR2-dependent event. The conditioned medium of PKR2-cardiomyocytes induced fenestration of endothelial cells and inhibited tube-like formations. These endotheliopathies were blocked by either depleting activin A or sENG from conditioned medium or by using 2 pharmacological inhibitors, follistatin, and TRC105. In addition, similar endotheliopathies were produced by exogenous administration of activin A and ENG. Prolonged exposure to prokineticin-2 in PKR2-cardiomyocytes increased cell volume by the PKR2/Gα 12/13 /ERK5-pathway. Activation of the PKR2/Gα 12/13 /matrix metalloprotease-pathway promoted both activin A and sENG release. This study reveals that pressure overload–mediated PKR2 signaling in cardiomyocytes contributes to cardiac hypertrophy through autocrine signaling, and vascular rarefaction via cardiac cytokine-mediated cardiomyocyte–endothelial cell communications. Our results may contribute to the development of potential therapeutic targets for heart failure.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

Abstract 65: Regulation of Cardiac Hypertrophy and Dilated Cardiomyopathy by CIP

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhan-Peng Huang ◽  
Masaharu Kataoka ◽  
Jinghai Chen ◽  
Da-Zhi Wang
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Premature Death ◽  
Marker Genes ◽  
Ontology Term ◽  
Hypertrophic Growth

Cardiac hypertrophy is one of the primary responses of the heart to pathophysiological stress. However, the mechanism of the transition from compensative hypertrophic growth to cardiac dilation is poor understood. Recently, we identified a cardiac-specific expressed gene CIP. The expression of CIP is unchanged in hypertrophic heart but significantly down-regulated in dilated hearts, suggesting CIP may play an important role in the transition from cardiac hypertrophy to dilated cardiomyopathy. We generated CIP knockout mice and found that CIP is dispensable for cardiac development. Interestingly, CIP-null mutant mice developed severe cardiac dilation 4 weeks after TAC (transverse aortic constriction) surgery, while control mice were still at the stage of compensative hypertrophic growth. Echocardiography and histological examinations showed that mutant hearts had enlarged chamber with thinner ventricle wall and decreased cardiac performance compared to controls. The expression of marker genes of cardiac disease, BNP and Myh7, was elevated. Consistently, deletion of CIP in Myh6-CnA transgenic mice result in premature death, displaying severe left ventricle dilation. Conversely, cardiac-specific CIP overexpression inhibited pressure overload-induced cardiac hypertrophy. CIP transgenic mice exhibit decreased ventricle weight/body weight ratio, decreased cardiomyocyte cross-section area and repressed expression of hypertrophic related marker genes. CIP overexpression also protected the heart from developing cardiac dilation and preserved the cardiac function after prolonged pressure overload. We performed unbiased microarray assay to document the transcriptome in CIP knockout and control mice which were subjected to pressure overload (TAC). The analysis of Gene Ontology term indicated the Negative Regulation of Apoptosis was down-regulated while the Collagen/Extracellular Structure Organization was up-regulated in CIP-null hearts under TAC condition. In summary, our studies established CIP as a key regulator of the transition from cardiac hypertrophy to dilated cardiomyopathy. The protective effect of CIP in cardiac remodeling indicates that CIP could become a therapeutic target for cardiac diseases.

Abstract 206: A New MicroRNA Family Regulating Cardiac Autophagy and Hypertrophy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Thomas Thum ◽  
Shashi K Gupta ◽  
Ahmet Ucar ◽  
Jan Fiedler ◽  
Leon DeWindt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Hypertrophy ◽  
Cardiac Failure ◽  
Pressure Overload ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy ◽  
Microrna Family ◽  
Causes Of Mortality ◽  
Necessary And Sufficient

Pathologic growth of cardiomyocytes and derailed autophagy are major determinants for the development of heart failure, one of the leading medical causes of mortality worldwide. Here, we show the microRNA (miRNA)-212/132 family to regulate hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli lead to the upregulation of miR-212 and miR-132 expression in cardiomyocytes, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and lethality in mice. Mechanistically, both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and impaired autophagic response upon starvation. Pharmacologic miRNA inhibition by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

scholarly journals Remodeling of the peripheral cardiac conduction system in response to pressure overload

2012 ◽  
Vol 302 (8) ◽  
pp. H1712-H1725 ◽  
Author(s):  
Brett S. Harris ◽  
Catalin F. Baicu ◽  
Nicole Haghshenas ◽  
Harinath Kasiganesan ◽  
Dimitri Scholz ◽  
...  
Keyword(s):  
Ion Channel ◽  
Gap Junction ◽  
Normal Sinus Rhythm ◽  
Expression Patterns ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Hypertrophic Growth ◽  
Transaortic Constriction

How chronic pressure overload affects the Purkinje fibers of the ventricular peripheral conduction system (PCS) is not known. Here, we used a connexin (Cx)40 knockout/enhanced green fluorescent protein knockin transgenic mouse model to specifically label the PCS. We hypothesized that the subendocardially located PCS would remodel after chronic pressure overload and therefore analyzed cell size, markers of hypertrophy, and PCS-specific Cx and ion channel expression patterns. Left ventricular hypertrophy with preserved systolic function was induced by 30 days of surgical transaortic constriction. After transaortic constriction, we observed that PCS cardiomyocytes hypertrophied by 23% ( P < 0.05) and that microdissected PCS tissue exhibited upregulated markers of hypertrophy. PCS cardiomyocytes showed a 98% increase in the number of Cx40-positive gap junction particles, with an associated twofold increase in gene expression ( P < 0.05). We also identified a 50% reduction in Cx43 gap junction particles located at the interface between PCS cardiomyocytes and the working cardiomyocyte. In addition, we measured a fourfold increase of an ion channel, hyperpolarization-activated cyclic nucleotide-gated channel (HCN)4, throughout the PCS ( P < 0.05). As a direct consequence of PCS remodeling, we found that pressure-overloaded hearts exhibited marked changes in ventricular activation patterns during normal sinus rhythm. These novel findings characterize PCS cardiomyocyte remodeling after chronic pressure overload. We identified significant hypertrophic growth accompanied by modified expression of Cx40, Cx43, and HCN4 within PCS cardiomyocytes. We found that a functional outcome of these changes is a failure of the PCS to activate the ventricular myocardium normally. Our findings provide a proof of concept that pressure overload induces specific cellular changes, not just within the working myocardium but also within the specialized PCS.

scholarly journals Cooperative Binding of ETS2 and NFAT Link Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy

Circulation ◽  
2021 ◽  
Author(s):  
Yuxuan Luo ◽  
Nan Jiang ◽  
Herman I. May ◽  
Xiang Luo ◽  
Anwarul Ferdous ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Target Genes ◽  
Critical Role ◽  
Pressure Overload ◽  
Marker Genes ◽  
Activated T Cells ◽  
Hypertrophic Growth ◽  
Conditional Deletion ◽  
Extracellular Signal

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. Methods: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. Conclusions: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.

scholarly journals Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth

2002 ◽  
Vol 22 (21) ◽  
pp. 7603-7613 ◽  
Author(s):  
Benjamin J. Wilkins ◽  
Leon J. De Windt ◽  
Orlando F. Bueno ◽  
Julian C. Braz ◽  
Betty J. Glascock ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Intrinsic Defect ◽  
Regulatory Pathway ◽  
Targeted Disruption ◽  
Activated T Cells ◽  
Hypertrophic Growth ◽  
Downstream Effectors

ABSTRACT A calcineurin-nuclear factor of activated T cells (NFAT) regulatory pathway has been implicated in the control of cardiac hypertrophy, suggesting one mechanism whereby alterations in intracellular calcium handling are linked to the expression of hypertrophy-associated genes. Although recent studies have demonstrated a necessary role for calcineurin as a mediator of cardiac hypertrophy, the potential involvement of NFAT transcription factors as downstream effectors of calcineurin signaling has not been evaluated. Accordingly, mice with targeted disruptions in NFATc3 and NFATc4 genes were characterized. Whereas the loss of NFATc4 did not compromise the ability of the myocardium to undergo hypertrophic growth, NFATc3-null mice demonstrated a significant reduction in calcineurin transgene-induced cardiac hypertrophy at 19 days, 26 days, 6 weeks, 8 weeks, and 10 weeks of age. NFATc3-null mice also demonstrated attenuated pressure overload- and angiotensin II-induced cardiac hypertrophy. These results provide genetic evidence that calcineurin-regulated responses require NFAT effectors in vivo.

scholarly journals p38α Mitogen-Activated Protein Kinase Plays a Critical Role in Cardiomyocyte Survival but Not in Cardiac Hypertrophic Growth in Response to Pressure Overload

2004 ◽  
Vol 24 (24) ◽  
pp. 10611-10620 ◽  
Author(s):  
Kazuhiko Nishida ◽  
Osamu Yamaguchi ◽  
Shinichi Hirotani ◽  
Shungo Hikoso ◽  
Yoshiharu Higuchi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Knockout Mice ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Pressure Overload ◽  
Mitogen Activated Protein Kinase ◽  
Hypertrophic Growth ◽  
Mitogen Activated Protein ◽  
Cardiomyocyte Survival

ABSTRACT The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38α is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38α in hearts. First, we generated mice with floxed p38α alleles and crossbred them with mice expressing the Cre recombinase under the control of the α-myosin heavy-chain promoter to obtain cardiac-specific p38α knockout mice. These cardiac-specific p38α knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38α plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

Mitochondrial biogenesis during pressure overload induced cardiac hypertrophy in adult rats

1995 ◽  
Vol 73 (5) ◽  
pp. 630-637 ◽  
Author(s):  
Mary L. Nishio ◽  
Olga I. Ornatsky ◽  
Elaine E. Craig ◽  
David A. Hood
Keyword(s):  
Cytochrome C ◽  
Cardiac Hypertrophy ◽  
Cytochrome C Oxidase ◽  
Mitochondrial Biogenesis ◽  
Molecular Chaperones ◽  
Protein Import ◽  
Pressure Overload ◽  
Sham Operation ◽  
Aortic Constriction ◽  
Hypertrophic Growth

Existing literature provides an equivocal picture of the behavior of mitochondrial synthesis during the time course of cardiac hypertrophy. Therefore, we examined the effect of cardiac hypertrophy on mitochondrial cytochrome c oxidase (CYTOX) activity, the content of CYTOX subunit VIc mRNA, and the expression of molecular chaperones. Adult male Sprague–Dawley rats were subjected to either abdominal aortic constriction to induce pressure overload (PO) or a sham operation (SH). Animals were studied 2, 4, 7, 14, 21, or 28 days after surgery. Aortic constriction resulted in a significant elevation in arterial pressure by 4 days after surgery. Significant (p < 0.05) hypertrophy was attained by 4 days and was stabilized at 37% between 7 and 28 days. CYTOX activity (U/g) did not differ significantly between PO and SH animals at either early (<7 days) or later time points, indicating that mitochondrial content increased in proportion to adaptive cellular hypertrophic growth. The concentration of the molecular chaperones HSP60 and GRP75 involved in mitochondrial protein import did not change with PO treatment. The levels of mRNAs encoding both CYTOX subunit VIc and HSP60 remained constant, in proportion to cardiac growth. This suggests that the accelerated synthesis of CYTOX and HSP60 during cardiac hypertrophy is regulated transcriptionally. The data help to resolve the controversy in the literature regarding mitochondrial biogenesis during moderate, stable cardiac hypertrophy, and they indirectly indicate that proportional mitochondrial synthesis relative to cellular hypertrophy is regulated at the transcriptional level.Key words: hypertension, cytochrome c oxidase, mRNA, cytochrome c oxidase subunits, aortic constriction, heat shock proteins, molecular chaperones.

Abstract 97: Induction of Hexosamine Biosynthetic Pathway Promotes Cardiac Hypertrophy through Activation of O-GlcNAcylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Diem H Tran ◽  
Jianping Li ◽  
Xiaoding Wang ◽  
Herman I May ◽  
Gabriele G Schiattarella ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Biosynthetic Pathway ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Mice Model ◽  
Hexosamine Biosynthetic Pathway ◽  
Hypertrophic Growth

Background & significance: Heart failure affects approximately 6 million Americans, with 5-year survival of 50%, which is responsible for a huge burden on the US economy and healthcare system. The relevance and significance of the metabolic alteration to the pathogenesis of pressure overload-induced cardiac hypertrophy and heart failure are largely unknown. The hexosamine biosynthetic pathway (HBP) that is linked to metabolism of glucose, fatty acids and amino acids, has been implicated in the pathophysiology of heart diseases. Methods & results: Thoracic aortic constriction (TAC) was performed to induce heart failure by pressure overload in mice. At the in vitro levels, treatment of phenylephrine (PE, 50 μM) was used to induce cellular hypertrophy in neonatal rat ventricular myocytes (NRVM). Our data revealed that all the enzymes of the HBP were upregulated while induction of hypertrophy at both in vivo and in vitro levels. Consistently, the intermediate product of the HBP was elevated in heart by afterload stress, as measured by metabolomics analyses. In the transgenic mice model for Gfat1, the rate-limiting enzyme of the HBP, we found more profound cardiac hypertrophy and cardiac remodeling in response to pressure overload. The increase of O-GlcNAc was also observed. In addition, the regulation of O-GlcNAcylation by specific targeting of two enzymes of the HBP (1 mM Alloxan, an inhibitor of OGT and 10 μM PUGNAc, an inhibitor of OGA) in NRVM suggested an involvement of the mTOR signaling in the activation of O-GlcNAc levels and the hypertrophy response. Targeting of the HBP by either specific siRNA or Gfat1 inhibitor (Azaserine, 5 μM) led to decrease in cellular hypertrophic response. Conclusions: Together, our data strongly suggest that the HBP participates in cardiac hypertrophic growth and pharmacologic targeting of the HBP may represent a novel approach to ameliorate pathological remodeling.

scholarly journals How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial

2017 ◽  
Vol 313 (5) ◽  
pp. H919-H930 ◽  
Author(s):  
Mordecai P. Blaustein
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Wild Type ◽  
Ouabain Binding ◽  
Transaortic Constriction ◽  
Endogenous Ouabain

Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive α2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of α2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α2-ouabain-resistant (R) mice in which the normally ouabain-resistant α1-Na+ pumps were mutated to an ouabain-sensitive (S) form (α1S/Sα2R/R or “SWAP” vs. wild-type or α1R/R α2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease.

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