Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

Gürgen, Dennis; Kusch, Angelika; Klewitz, Robin; Hoff, Uwe; Catar, Rusan; Hegner, Björn; Kintscher, Ulrich; Luft, Friedrich C.; Dragun, Duska

doi:10.1161/hypertensionaha.111.00276

Cited by 33 publications

(28 citation statements)

References 35 publications

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“…Specific sex differences in DOC/salt-induced cardiomyopathy are mediated by ER signalling [109]. mTOR (mammalian target of rapamycin) is involved in the ERβ regulation of cardiac fibrosis and hypertrophy in normotensive mice during mineralocorticoid excess, supporting a differential role for MR activation in males relative to females [110]. DOC/salt treatment exacerbates blood pressureindependent cardiac hypertrophy in male mice only [111].…”

Section: The Mr Is a Key Determinant Of Cardiac Fibrosismentioning

confidence: 99%

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

et al. 2013

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MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.

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Section: The Mr Is a Key Determinant Of Cardiac Fibrosismentioning

confidence: 99%

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

et al. 2013

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“…82, 83 The purported molecular mechanisms involve calcineurin degradation, 84 mTOR signaling, 85 regulation of phosphorylated p38 MAPK pathways. 86 and regulation of cardiomyocyte histone deacetylases.…”

Section: Estrogen and Ers In Myocardial Hypertrophymentioning

confidence: 99%

The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview

Luo

Kim

2016

Canadian Journal of Cardiology

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Sex differences in the onset and manifestation of cardiovascular diseases are well known, yet the mechanism behind this discrepancy remains obscure. Estrogen and its corresponding receptors have been studied for their positive salutary effects in females for decades. Estrogen protects the heart from various forms of stress, including cytotoxic, ischemic and hypertrophic stimuli. The postulated underlying mechanism is complex, and involves the actions of the hormone on the endothelium and myocardium. While the effects of estrogen on the coronary endothelium are well-described, delineation of the hormone’s action on cardiomyocytes is still evolving. The focus of this article is to review the accumulated literature and latest data on the role of estrogen and its receptors on cardiomyocytes, the contractile cellular units of the myocardium.

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“…Consistent with these findings, estradiol can impact seizure susceptibility (Scharfman and MacLusky, 2014; Reddy, 2017). In addition, several studies have identified sex difference in mTOR signaling in non-CNS tissues and functions (Gürgen et al, 2013; Miller et al, 2014; Baar et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

PTEN deletion increases hippocampal granule cell excitability in male and female mice

Santos

Pun

Arafa

et al. 2017

Neurobiology of Disease

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Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity.

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Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model

Cited by 33 publications

References 35 publications

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte

The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview

PTEN deletion increases hippocampal granule cell excitability in male and female mice

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