scholarly journals Cardiomyocyte-Specific Deletion of Orai1 Reveals Its Protective Role in Angiotensin-II-Induced Pathological Cardiac Remodeling

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1092 ◽  
Author(s):  
Sebastian Segin ◽  
Michael Berlin ◽  
Christin Richter ◽  
Rebekka Medert ◽  
Veit Flockerzi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Contractile Function ◽  
Calcium Entry ◽  
Cardiomyocyte Hypertrophy ◽  
Protective Function ◽  
Cellular Hypertrophy ◽  
Adult Cardiomyocytes ◽  
Embryonic Cardiomyocytes

Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo. Cellular hypertrophy induced by angiotensin-II in embryonic cardiomyocytes from Orai1-deficient mice was blunted in comparison to cells from litter-matched control mice. Due to lethality of mice with ubiquitous Orai1 deficiency and to selectively analyze the role of Orai1 in adult cardiomyocytes, we generated a cardiomyocyte-specific and temporally inducible Orai1 knockout mouse line (Orai1CM–KO). Analysis of cardiac contractility by pressure-volume loops under basal conditions and of cardiac histology did not reveal differences between Orai1CM–KO mice and controls. Moreover, deletion of Orai1 in cardiomyocytes in adult mice did not protect them from angiotensin-II-induced cardiac remodeling, but cardiomyocyte cross-sectional area and cardiac fibrosis were enhanced. These alterations in the absence of Orai1 go along with blunted angiotensin-II-induced upregulation of the expression of Myoz2 and a lack of rise in angiotensin-II-induced STIM1 and Orai3 expression. In contrast to embryonic cardiomyocytes, where Orai1 contributes to the development of cellular hypertrophy, the results obtained from deletion of Orai1 in the adult myocardium reveal a protective function of Orai1 against the development of angiotensin-II-induced cardiac remodeling, possibly involving signaling via Orai3/STIM1-calcineurin-NFAT related pathways.

scholarly journals Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice

2016 ◽  
Vol 118 (12) ◽  
pp. 1906-1917 ◽  
Author(s):  
Harmandeep Kaur ◽  
Mikito Takefuji ◽  
C.Y. Ngai ◽  
Jorge Carvalho ◽  
Julia Bayer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Single Cell ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Transcriptional Analysis ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Damage

Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear. Objective: To study the effect of CF ablation on cardiac remodeling. Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome–transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

scholarly journals PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

2016 ◽  
Vol 113 (45) ◽  
pp. E7116-E7125 ◽  
Author(s):  
Walter E. Knight ◽  
Si Chen ◽  
Yishuai Zhang ◽  
Masayoshi Oikawa ◽  
Meiping Wu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Causative Role ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Cardiac Myocyte Hypertrophy

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

scholarly journals miR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Que Wang ◽  
Xiaoxue Yu ◽  
Lin Dou ◽  
Xiuqing Huang ◽  
Kaiyi Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Left Ventricular Myocardium ◽  
Chronic Hypertension ◽  
Arylsulfatase B

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3′-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.

scholarly journals Macrophage-adipocyte communication and cardiac remodeling

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Gautham Yepuri ◽  
Syed Nurul Hasan ◽  
Ann Marie Schmidt ◽  
Ravichandran Ramasamy
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Underlying Mechanisms

In obesity complicated by hypertension, multicellular processes integrate to orchestrate cardiac fibrosis; the underlying mechanisms, however, remain elusive. In this issue of JEM, Cheng et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210252) describe adipocyte–macrophage collaboration to foster cardiac fibrosis through the actions of angiotensin II in obesity.

Abstract 1224: Rock1 Deletion Prevents Cardiac Dilation And Improves Contractile Function In Pathological Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jianjian Shi ◽  
Yi-Wei Zhang ◽  
Gerald W Dorn ◽  
Lei Wei
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Contractile Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Molecular Defect ◽  
Contractile Dysfunction ◽  
Adrenergic Stimulation ◽  
Compensatory Response

The development of left ventricular cardiomyocyte hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response. However, persistent stress eventually leads to dilated heart failure, which is a common cause of heart failure in human hypertensive and valvular heart disease. We have recently reported that ROCK1 homozygous knockout mice exhibited reduced cardiac fibrosis and cardiomyocyte apoptosis, while displayed a preserved compensatory hypertrophic response to pressure overload. Here, we tested effects of ROCK1 deficiency on cardiac hypertrophy, dilation, and dysfunction by using the transgenic Gαq mice which represent a well-characterized and highly relevant genetic mouse model of pathological hypertrophy and heart failure. We have shown that ROCK1 deletion prevented left ventricular dilation and contractile dysfunction in Gαq mice under basal condition. ROCK1 deletion also partially rescued bradycardia and improved contractile response to β-adrenergic stimulation in Gαq mice. Although the development of cardiomyocyte hypertrophy was not affected, ROCK1 deletion in Gαq mice resulted in a concentric hypertrophic phenotype associated with reduced induction of hypertrophic markers. Finally, ROCK1 deletion prevented down-regulation of type V adenylyl cyclase expression, which is a critical molecular defect contributing to the impaired β-adrenergic signaling in Gαq mice. The present study establishes for the first time a role for ROCK1 in cardiac dilation and contractile dysfunction.

scholarly journals Inhibition of microRNA-155 ameliorates cardiac fibrosis in the process of angiotensin II-induced cardiac remodeling

2017 ◽  
Vol 16 (5) ◽  
pp. 7287-7296 ◽  
Author(s):  
Yuzhen Wei ◽  
Xiaofei Yan ◽  
Lianhua Yan ◽  
Fen Hu ◽  
Wenhan Ma ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis

scholarly journals Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

2011 ◽  
Vol 301 (3) ◽  
pp. H984-H993 ◽  
Author(s):  
Eric E. Essick ◽  
Noriyuki Ouchi ◽  
Richard M. Wilson ◽  
Koji Ohashi ◽  
Joanna Ghobrial ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Leucine Incorporation ◽  
Ang Ii ◽  
Adult Rat

Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 μg/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1–200 μM). ARVM hypertrophy was measured by [3H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg−1·day−1 for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H2O2-induced p-ERK activity and NF-κB activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-κB activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS-induced cardiac remodeling.

P748Afterload-induced TRIF-dependent signaling promotes fibrosis but not cardiomyocyte hypertrophy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S I Bettink ◽  
A Kazakov ◽  
C Koerbel ◽  
M Boehm ◽  
B Scheller ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Myocardial Hypertrophy ◽  
Interstitial Fibrosis ◽  
Early Stage ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Post Intervention ◽  
Cellular Hypertrophy

Abstract Background Pressure overload dependent cardiac remodeling is characterized by a continuous functional loss of cardiomyocytes, cardiomyocyte hypertrophy, cell death and fibrosis. The relevance of the MyD88- and NFκB-independent inflammatory TRIF (TIR-domain-containing adapter protein inducing IFN-β) signaling pathway in myocardial hypertrophy is incompletely understood. Methods and results The murine model of afterload induced myocardial hypertrophy (trans-aortic constriction, TAC) was used to investigate the time dependent chemokine expression in C57Bl/6J Wild type (WT) mice after intervention. Myd88- as well as TRIF-dependent chemokines reached their expression maximum at d7 post intervention. This time point was determined for further investigations on TRIF knockout-mice (TRIF−/−) compared to WT mice. While left ventricular (LV) mRNA-expression of TNFalpha and IL6 was upregulated in TRIF−/− mice, CXCL10, CXCL11, RANTES and pathway molecule IRF3 remained unchanged. In the stage of established hypertrophy (35 days after TAC) cytokine levels returned to baseline in WT as well as in TRIF−/− mice. Cellular hypertrophy (increase in cardiomyocyte size) as well as echocardiographic determined increase of LV mass was similar in TRIF−/− and WT mice at d7 as well as at d35 after TAC. Additionally at d7 and d35 the fractional shortening function didn't show any differences between the groups after TAC. On the other hand LV interstitial fibrosis (determined by collagen content) was significantly less distinct in TRIF−/− mice (1.4±0.2%) than in WT mice (2.3±0.3%, (p<0.01 TRIF−/− vs. WT) at d7 following TAC. According to that TGFbeta protein expression was more pronounced in WT (318±85% of sham-operated controls) than in TRIF−/− mice (111±15% of sham-operated controls; p<0.05 TRIF−/− vs. WT). These differences in fibrosis and TGFbeta remained at d35. Even the hydroxyproline concentration was higher in LV tissue of the WT mice than in the TRIF−/− mice d35 after TAC (WT: 93.4±7.7μM, TRIF−/− 54.8±9.0μM, p<0.5 TRIF−/− vs. WT). The expression of TGFbeta signaling pathway associated SMAD proteins (SMAD 3, pSMAD3, SMAD4) was up to two fold higher in WT mice than in TRIF−/− mice. Additionally expression of antifibrotic miR29b was more pronounced in TRIF−/− mice (2.34±0.71) than in WT mice (0.98±0.08) after TAC d7. Conclusion In afterload induced hypertrophy TRIF-dependent signaling doesn't influence cardiomyocyte hypertrophy. But TRIF plays an important role in the regulation of fibrosis in pressure overload dependent remodeling. Through the modulation of the TGF-beta signaling pathway and antifibrotic microRNAs TRIF signaling is involved in the development of interstitial fibrosis. Especially in the early stage of the cardiac remodeling. Acknowledgement/Funding KFO196

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