ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice

Cardiac hypertrophy in humans can progress to cardiac failure if the underlying impetus is poorly controlled. An important direct stimulator of hypertrophy and its progression is the angiotensin II (AngII) peptide. AngII also causes hypertension that indirectly contributes to cardiac hypertrophy. Others and we have shown that estrogens acting through the estrogen receptor (ER)-β can inhibit AngII-induced or other forms of cardiac hypertrophy in mice. However, the proliferative effects of estrogen in breast and uterus that promote the development of malignancy preclude using the steroid to prevent cardiac disease progression. We therefore tested whether an ERβ selective agonist, β-LGND2, can prevent hypertension and cardiac pathology in female mice. AngII infusion over 3 weeks significantly stimulated systolic and diastolic hypertension, cardiac hypertrophy, and cardiac fibrosis, all significantly prevented by β-LGND2 in wild-type but not in ERβ genetically deleted mice. AngII stimulated the Akt kinase to phosphorylate and inhibit the glycogen synthase kinase-3β kinase, leading to GATA4 transcription factor activation and hypertrophic mRNA expression. As a novel mechanism, all these actions were opposed by estradiol and β-LGND2. Our findings provide additional understanding of the antihypertrophic effects of ERβ and serve as an impetus to test specific receptor agonists in humans to prevent the worsening of cardiovascular disease.

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Abstract 61: Ablation of BK Ca Channels Results in Cardiac Hypertrophy

Circulation Research ◽

10.1161/res.119.suppl_1.61 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Harpreet Singh ◽

Kajol Shah ◽

Devsena Ponnalagu ◽

Sanjay Chandrasekhar ◽

Andrew R Kohut ◽

...

Keyword(s):

Ejection Fraction ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Structural Changes ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Interventricular Septum ◽

Wild Type

Expression and activation of the large conductance calcium and voltage-gated potassium (BK Ca ) channels encoded by Kcnma1 gene is shown to be vital in cardioprotection from ischemia-reperfusion injury. BK Ca channels present in SA node cells regulate the heart rate, and in blood vessels play an active role in vascular relaxation. However, the role of BK Ca in regulation of structure and function of the heart is not fully-established. Using Kcnma1 -/- mice, we have observed structural changes in cardiomyocytes and compromised cardiac function as compared to wild type mice. Absence of BK Ca resulted in significant increase in size of adult cardiomyocytes (from 7.95 + 0.1 um 2 to 9.68 + 0.1 um 2 , p < 0.01, n=480 cells each) and also increased cardiac fibrosis. Further to determine underlying signaling mechanisms in cardiac hypertrophy, we performed microarray analysis of RNAs isolated from wild type and Kcnma1 -/- mice (n=3) hearts. We found up regulation of a class of cardiac hypertrophy markers (myosin variants) and changes in the expression of several mitochondrial genes (such as ND4) directly associated with heart diseases in Kcnma1 -/- mice. To evaluate the functional consequence of absence of BK Ca , we performed high-resolution echocardiography on wild type and Kcnma1 -/- mice. Under anesthesia (1.5% isoflurane), left ventricle of Kcnma1 -/- mice showed significant reduction (p < 0.05) in ejection fraction (56 + 2 %, n=7) as compared to wild type (74 + 3 %, n=6) as well as fractional shortening (23 + 3 %, n=7, and 39 + 3 %, n=6, respectively). Similarly, right ventricle had a lower ejection fraction (35.7 + 4% vs 56.9 + 5 %, n > 5) in Kcnma1 -/- as compared to wild type mice. In agreement with our histopathology and microarray data, Kcnma1 -/- mice showed increased posterior wall thickness (0.75 + 0.3 mm vs 0.62 + 0.1 mm) and interventricular septum thickness (0.83 + 0.4 mm, n=7 vs 0.68 + 0.3 mm, n=6) . Together, these data imply that BK Ca plays a direct role in cardiac hypertrophy and cardiac function.

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Knockout of the Prostaglandin E2 Receptor Subtype 3 Promotes Eccentric Cardiac Hypertrophy and Fibrosis in Mice

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248416642520 ◽

2016 ◽

Vol 22 (1) ◽

pp. 71-82 ◽

Cited By ~ 5

Author(s):

Shuang Liu ◽

Yawei Ji ◽

Jian Yao ◽

Xiaodan Zhao ◽

Hu Xu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Messenger Rna ◽

Cardiac Fibrosis ◽

Glycogen Synthase ◽

Mrna Level ◽

Matrix Metalloproteinase 2 ◽

Prostaglandin E ◽

Receptor Subtype ◽

The Impact ◽

Subtype 3

Background: Prostaglandin E2 receptor subtype 3 (EP3), a Gi protein-coupled receptor activated by prostaglandin E2, plays a particular role in cardioprotection. This study aimed to investigate the impact of EP3 deletion on cardiac remodeling and further elucidate the related involvement of possible signaling pathways. Methods and Results: The animals used were EP3 receptor knockout (EP3KO) mice and wild-type (WT) litter mate controls at 16-18 weeks old. The high-resolution echocardiography and weight index indicated that eccentric cardiac hypertrophy might occur in EP3KO mice, which were having worse cardiac function than WT litter mates. Isolated adult myocytes from EP3KO hearts showed spontaneous lengthening. Cardiac fibrosis was observed in EP3KO mice through Masson trichrome staining. The elevated messenger RNA (mRNA) level in matrix genes and the reduced mRNA, protein, and activity levels of matrix metalloproteinase 2 (MMP-2) indicated an increased synthesis and suppressed degradation of matrix collagen in EP3KO mice. The phosphorylation level of extracellular signal-regulated kinase (ERK) 1/2 protein was reduced in the cardiac tissue of EP3KO mice, accompanied by no significant change in the protein level of total ERK1/2, total p38, phospho-p38, glycogen synthase kinase-3β (GSK3β), phospho-GSK3β, and calcineurin (CaN) as well as CaN activity. Conclusion: EP3 knockout in cardiac tissues could induce eccentric cardiac hypertrophy and cardiac fibrosis at 16-18 weeks old. These effects of EP3 knockout might be regulated through inactivating MAPK/ERK pathway and affecting the MMP-2 expression. Overall, PGE2-EP3 is necessary to maintain the normal growth and development of the heart.

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CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01114.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. H538-H547 ◽

Cited By ~ 58

Author(s):

Jing Xu ◽

Song-Chang Lin ◽

Jiyuan Chen ◽

Yuanxin Miao ◽

George E. Taffet ◽

...

Keyword(s):

Bone Marrow ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Knockout Mice ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Systolic Function ◽

Left Ventricular ◽

Collagen I ◽

Wild Type

Angiotensin II plays an important role in the development of cardiac hypertrophy and fibrosis, but the underlying cellular and molecular mechanisms are not completely understood. Recent studies have shown that bone marrow-derived fibroblast precursors are involved in the pathogenesis of cardiac fibrosis. Since bone marrow-derived fibroblast precursors express chemokine receptor, CCR2, we tested the hypothesis that CCR2 mediates the recruitment of fibroblast precursors into the heart, causing angiotensin II-induced cardiac fibrosis. Wild-type and CCR2 knockout mice were infused with angiotensin II at 1,500 ng·kg−1·min−1. Angiotensin II treatment resulted in elevated blood pressure and cardiac hypertrophy that were not significantly different between wild-type and CCR2 knockout mice. Angiotensin II treatment of wild-type mice caused prominent cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors expressing the hematopoietic markers, CD34 and CD45, and the mesenchymal marker, collagen I. However, angiotensin II-induced cardiac fibrosis and accumulation of bone marrow-derived fibroblast precursors in the heart were abrogated in CCR2 knockout mice. Furthermore, angiotensin II treatment of wild-type mice increased the levels of collagen I, fibronectin, and α-smooth muscle actin in the heart, whereas these changes were not observed in the heart of angiotensin II-treated CCR2 knockout mice. Functional studies revealed that the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and left ventricular dilatation in angiotensin II-treated CCR2 knockout mice. Our data demonstrate that CCR2 plays a pivotal role in the pathogenesis of angiotensin II-induced cardiac fibrosis through regulation of bone marrow-derived fibroblast precursors.

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Androgen Contributes to Gender-Related Cardiac Hypertrophy and Fibrosis in Mice Lacking the Gene Encoding Guanylyl Cyclase-A

Endocrinology ◽

10.1210/en.2003-0816 ◽

2004 ◽

Vol 145 (2) ◽

pp. 951-958 ◽

Cited By ~ 55

Author(s):

Yuhao Li ◽

Ichiro Kishimoto ◽

Yoshihiko Saito ◽

Masaki Harada ◽

Koichiro Kuwahara ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Guanylyl Cyclase ◽

Cardiac Fibrosis ◽

Receptor Gene ◽

Pressure Change ◽

Cardiac Mass ◽

Wild Type ◽

Gene Encoding ◽

Androgen Receptor Antagonist

Abstract Myocardial hypertrophy and extended cardiac fibrosis are independent risk factors for congestive heart failure and sudden cardiac death. Before age 50, men are at greater risk for cardiovascular disease than age-matched women. In the current studies, we found that cardiac hypertrophy and fibrosis were significantly more pronounced in males compared with females of guanylyl cyclase-A knockout (GC-A KO) mice at 16 wk of age. These gender-related differences were not seen in wild-type mice. In the further studies, either castration (at 10 wk of age) or flutamide, an androgen receptor antagonist, markedly attenuated cardiac hypertrophy and fibrosis in male GC-A KO mice without blood pressure change. In contrast, ovariectomy (at 10 wk of age) had little effect. Also, chronic testosterone infusion increased cardiac mass and fibrosis in ovariectomized GC-A mice. None of the treatments affected cardiac mass or the extent of fibrosis in wild-type mice. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, TGF-β1, TGF-β3, angiotensinogen, and angiotensin converting enzyme in the ventricles of male GC-A KO mice was substantially decreased by castration. The gender differences were virtually abolished by targeted deletion of the angiotensin II type 1A receptor gene (AT1A). Neither castration nor testosterone administration induced any change in the cardiac phenotypes of double-KO mice for GC-A and AT1A. Thus, we suggest that androgens contribute to gender-related differences in cardiac hypertrophy and fibrosis by a mechanism involving AT1A receptors and GC-A.

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Estrogen Inhibits Cardiac Hypertrophy: Role of Estrogen Receptor-β to Inhibit Calcineurin

Endocrinology ◽

10.1210/en.2008-0133 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3361-3369 ◽

Cited By ~ 114

Author(s):

Ali Pedram ◽

Mahnaz Razandi ◽

Dennis Lubahn ◽

Jinghua Liu ◽

Mani Vannan ◽

...

Keyword(s):

Estrogen Receptor ◽

Cardiac Hypertrophy ◽

Protein Expression ◽

Cardiac Fibrosis ◽

Interacting Protein ◽

Female Mice ◽

Cellular Effects ◽

Gene And Protein Expression ◽

Β Receptor

Estrogen has been reported to prevent development of cardiac hypertrophy in female rodent models and in humans. However, the mechanisms of sex steroid action are incompletely understood. We determined the cellular effects by which 17β-estradiol (E2) inhibits angiotensin II (AngII)-induced cardiac hypertrophy in vivo. Two weeks of angiotensin infusion in female mice resulted in marked hypertrophy of the left ventricle, exacerbated by the loss of ovarian steroid hormones from oophorectomy. Hypertrophy was 51% reversed by the administration of E2 (insertion of 0.1 mg/21-d-release tablets). The effects of E2 were mainly mediated by the estrogen receptor (ER) β-isoform, because E2 had little effect in ERβ-null mice but comparably inhibited AngII-induced hypertrophy in wild-type or ERα-null mice. AngII induced a switch of myosin heavy chain production from α to β, but this was inhibited by E2 via ERβ. AngII-induced ERK activation was also inhibited by E2 through the β-receptor. E2 stimulated brain natriuretic peptide protein expression and substantially prevented ventricular interstitial cardiac fibrosis (collagen deposition) as induced by AngII. Importantly, E2 inhibited calcineurin activity that was stimulated by AngII, related to E2 stimulating the modulatory calcineurin-interacting protein (MCIP) 1 gene and protein expression. E2 acting mainly through ERβ mitigates the important signaling by AngII that produces cardiac hypertrophy and fibrosis in female mice.

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Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

Hypertension ◽

10.1161/hyp.78.suppl_1.p140 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Chandramohan Ramasamy ◽

Umadevi Subramanian ◽

Kailash N Pandey

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Growth Factor ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Cardiac Fibrosis ◽

Left Ventricular ◽

Mutant Mice ◽

Null Mutant ◽

Wild Type

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p<0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p<0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p<0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

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Endogenous Relaxin Does Not Affect Chronic Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis

Endocrinology ◽

10.1210/en.2007-1220 ◽

2007 ◽

Vol 149 (2) ◽

pp. 476-482 ◽

Cited By ~ 31

Author(s):

Qi Xu ◽

Edna D. Lekgabe ◽

Xiao-Ming Gao ◽

Ziqiu Ming ◽

Geoffrey W. Tregear ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Left Ventricular ◽

Wild Type ◽

Gene Profile ◽

Aortic Constriction ◽

Littermate Control ◽

Lv Remodeling ◽

Hypertrophic Myocardium

The effect of endogenous relaxin on the development of cardiac hypertrophy, dysfunction, and fibrosis remains completely unknown. We addressed this question by subjecting relaxin-1 deficient (Rln1−/−) and littermate control (Rln1+/+) mice of both genders to chronic transverse aortic constriction (TAC). The extent of left ventricular (LV) remodeling and dysfunction were studied by serial echocardiography over an 8-wk period and by micromanometry. The degree of hypertrophy was estimated by LV weight, cardiomyocyte size, and expression of relevant genes. Cardiac fibrosis was determined by hydroxyproline assay and quantitative histology. Expression of endogenous relaxin during the course of TAC was also examined. In response to an 8-wk period of pressure overload, TAC mice of both genotypes developed significant LV hypertrophy, fibrosis, hypertrophy related gene profile, and signs indicating congestive heart failure when compared with respective sham controls. The severity of these alterations was not statistically different between the two genotypes of either gender. Relaxin mRNA expression was up-regulated, whereas that of its receptor was unchanged in the hypertrophic myocardium of wild-type mice. Collectively, the extent of pressure overload-induced LV hypertrophy, fibrosis, and dysfunction were comparable between Rln1+/+ and Rln1−/− mice. Thus, although up-regulated in its expression, endogenous relaxin had no significant effect on the progression of cardiac maladaptation and dysfunction in the setting of chronic pressure overload.

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Sex Differences in Dopamine Receptor Signaling in Fmr1 Knockout Mice: A Pilot Study

Brain Sciences ◽

10.3390/brainsci11111398 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1398

Author(s):

Anlong Jiang ◽

Le Wang ◽

Justin Y. D. Lu ◽

Amy Freeman ◽

Charlie Campbell ◽

...

Keyword(s):

Sex Differences ◽

Glycogen Synthase ◽

Genetic Disorder ◽

D2 Receptor ◽

D1 Receptor ◽

Variable Degree ◽

Wild Type ◽

Female Mice ◽

Dopamine Signaling ◽

Gsk 3Β

Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently in males and females, including abnormalities in the dopamine system that are also seen in Fmr1-knockout (KO) mice. We investigated sex differences in dopamine signaling in Fmr1-KO mice in response to L-stepholidine, a dopamine D1 receptor agonist and D2 receptor antagonist. We found significant sex differences in basal levels of phosphorylated protein kinase A (p-PKA) and glycogen synthase kinase (GSK)-3β in wild type mice that were absent in Fmr1-KO mice. In wild-type mice, L-stepholidine increased p-PKA in males but not female mice, decreased p-GSK-3 in female mice and increased p-GSK-3 in male mice. Conversely, in Fmr1-KO mice, L-stepholidine increased p-PKA and p-GSK-3β in females, and decreased p-PKA and p-GSK-3β in males.

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Chemotaxis and Transcription Factor Activation of Wild-Type and CCR6-Transfected RLE-6TN

Pneumologie ◽

10.1055/s-0032-1329813 ◽

2012 ◽

Vol 66 (11) ◽

Author(s):

K Hoehne ◽

H Eibel ◽

M Grimm ◽

M Idzko ◽

J Müller-Quernheim ◽

...

Keyword(s):

Transcription Factor ◽

Wild Type ◽

Transcription Factor Activation

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Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00914.2020 ◽

2021 ◽

Author(s):

Hadis Shakeri ◽

Jente R.A. Boen ◽

Sofie De Moudt ◽

Jhana O. Hendrickx ◽

Arthur J.A. Leloup ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiac Fibrosis ◽

Separate Experiment ◽

No Production ◽

Ang Ii ◽

Wild Type ◽

Paracrine Factor ◽

Renal Hypertrophy ◽

Neuregulin 1 ◽

Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

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