Sex-specific regulation of collagen I and III expression by 17β-Estradiol in cardiac fibroblasts: role of estrogen receptors

Dworatzek, Elke; Mahmoodzadeh, Shokoufeh; Schriever, Cindy; Kusumoto, Kana; Kramer, Lisa A.; Santos, Gabriela Leão; Fliegner, Daniela; Leung, Yuet-Kin; Ho, Shuk‐Mei; Zimmermann, Wolfram‐Hubertus; Lutz, Susanne; Regitz‐Zagrosek, Vera

doi:10.1093/cvr/cvy185

Cited by 85 publications

(68 citation statements)

References 51 publications

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“…This allowed us to compare the effects of Fasudil and H1152P, to demonstrate the concentration-dependent effect of SR-3677, to confirm that ROCKs play a role downstream of TGF-β in cardiac fibroblasts behaviour as suggested before [10], and to validate the importance of ROCKdependent signalling events like the actin-MRTF-LOX regulation. In addition to the presented pharmacological study we have demonstrated in the past that ECT can be prepared from male and female cells to study sex-differences in cardiac fibrosis and from virally transduced cells allowing loss-and gain-of function studies [15,18,30,42].…”

Section: Discussionmentioning

confidence: 99%

“…We perform linear ultimate destructive tensile measurements in order to obtain information on tissue stiffness (Young's modulus, slope of the elastic region of the stress-strain curve) and on the strain to failure point reflecting the maximal extensibility of the tissue. We have previously demonstrated that this model is suitable to perform gain and loss of function experiments as well as small molecule studies [15,18,30].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…Moreover, the estradiol could regulate ECM turnover by affecting the expression of MMP-2, which in turn is associated with altered ventricular remodeling in different cardiovascular pathologies (Dworatzek et al, 2019).…”

Section: Pro-fibrotic Triggersmentioning

confidence: 99%

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

et al. 2020

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Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.

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“…However, this possible protective effect of oestrogens is lost with the lack of oestrogens after menopause, possibly leading to increased perivascular fibrosis and subsequent microvascular stiffening. Oestrogens also inhibit collagen I and III deposition through activation of oestrogen receptor (ER) α [30], while androgens such as testosterone promote the deposition of collagen via increasing TGF-β production [31]. This may also contribute to increased perivascular fibrosis in women after menopause.…”

Section: Structural and Functional Alterations In Microvascular Diseasementioning

confidence: 99%

Sex-Specific Aspects in the Pathophysiology and Imaging of Coronary Macro- and Microvascular Disease

Groepenhoff

Bots

Kessler

et al. 2019

J. of Cardiovasc. Trans. Res.

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Sex differences in coronary artery disease (CAD) are well established, with women presenting with non-obstructive CAD more often than men do. However, recent evidence has identified coronary microvascular dysfunction as the underlying cause for cardiac complaints, yet sex-specific prevalence numbers are inconclusive. This review summarises known sex-specific aspects in the pathophysiology of both macro-and microvascular dysfunction and identifies currently existing knowledge gaps. In addition, this review describes current diagnostic approaches and whether these should take underlying sex differences into account by, for example, using different techniques or cut-off values for women and men. Future research into both innovation of imaging techniques and perfusion-related sex differences is needed to fill evidence gaps and enable the implementation of the available knowledge in daily clinical practice.

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Sex-specific regulation of collagen I and III expression by 17β-Estradiol in cardiac fibroblasts: role of estrogen receptors

Abstract: The mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERβ signaling in CFs.

Cited by 85 publications

References 51 publications

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

Sex-Specific Aspects in the Pathophysiology and Imaging of Coronary Macro- and Microvascular Disease

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