Modeling the Interplay of Sex Hormones in Cardiac Hypertrophic Signaling DOI Creative Commons

Adhithi Lakshmikanthan,

Marsha Kay,

Pim J. A. Oomen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Biological sex plays a crucial role in the outcomes of cardiac health and therapies. Sex hormones are known to strongly influence remodeling through intracellular signaling pathways, yet their underlying mechanisms remain unclear. To address this need, we developed validated logic-based systems biology model cardiomyocyte hypertrophy that, for first time, incorporates effects both estradiol (E2) testosterone (T) alongside well-established hypertrophic stimuli (Strain, angiotensin II (AngII), endothelin-1 (ET-1)). We qualitatively literature data with 84% agreement. Quantitative validation was done by simulating impact inputs (E2, T, Strain, AngII, ET-1) on hypertrophy, captured as change CellArea. perturbed examine differential response identify changes influential sensitive downstream nodes male, pre-menopausal female, post-menopausal female condition. Our results suggest that T has greater than E2. This increases our understanding which can aid developing more effective therapies all patients. Differences between male hearts extend far beyond size structure. play key roles sex-specific via pathways. Understanding how these is critical effective, approaches cardiovascular care. Logic-based models have proven useful quantifying analyzing complex intricate network dynamics various cell types. leverage method develop which, includes effect testosterone. Considering combined important because women men varying concentrations throughout lives. The based previously published studies. then investigated differences pre- men.

Язык: Английский

Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure DOI Creative Commons
Andrew L. Koenig,

Irina Shchukina,

Junedh M. Amrute

и другие.

Nature Cardiovascular Research, Год журнала: 2022, Номер 1(3), С. 263 - 280

Опубликована: Март 16, 2022

Heart failure represents a major cause of morbidity and mortality worldwide. Single-cell transcriptomics have revolutionized our understanding cell composition associated gene expression. Through integrated analysis single-cell single-nucleus RNA-sequencing data generated from 27 healthy donors 18 individuals with dilated cardiomyopathy, here we define the failing human heart. We identify cell-specific transcriptional signatures age heart reveal emergence disease-associated states. Notably, cardiomyocytes converge toward common states, whereas fibroblasts myeloid cells undergo dramatic diversification. Endothelial pericytes display global shifts without changes in complexity. Collectively, findings provide comprehensive cellular transcriptomic landscape failure, type-specific programs states establish valuable resource for investigation failure.

Язык: Английский

Процитировано

270
Vascular endothelial cell development and diversity DOI Open Access
Emily Trimm, Kristy Red‐Horse

Nature Reviews Cardiology, Год журнала: 2022, Номер 20(3), С. 197 - 210

Опубликована: Окт. 5, 2022

Язык: Английский

Процитировано

260
Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes DOI Open Access
Vera Regitz‐Zagrosek, Cathérine Gebhard

Nature Reviews Cardiology, Год журнала: 2022, Номер 20(4), С. 236 - 247

Опубликована: Окт. 31, 2022

Язык: Английский

Процитировано

170
Hearts apart: sex differences in cardiac remodeling in health and disease DOI Creative Commons
Thomas G. Martin, Leslie A. Leinwand

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(13)

Опубликована: Июнь 30, 2024

Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease the number one cause death worldwide both men women, differences exist at organ cellular scales, affecting clinical presentation, diagnosis, treatment. In this Review, we highlight baseline cardiac structure, function, signaling discuss contribution hormones chromosomes to these characteristics. The a remarkably plastic rapidly responds physiological pathological cues by modifying form function. nature extent remodeling response stimuli are often dependent on biological sex. We organ- molecular-level adaptive from pressure volume overload, ischemia, genetic disease. Finally, offer perspective key future directions for research into differences.

Язык: Английский

Процитировано

20
Mass Spectrometry-Based Atlas of Extracellular Matrix Proteins across 25 Mouse Organs DOI
Maxwell C. McCabe, Anthony J. Saviola, Kirk C. Hansen

и другие.

Journal of Proteome Research, Год журнала: 2023, Номер 22(3), С. 790 - 801

Опубликована: Фев. 10, 2023

The extracellular matrix (ECM) is a critical non-cellular component of multicellular organisms containing variety proteins, glycoproteins, and proteoglycans which have been implicated in wide essential biological processes, including development, wound healing, aging. Due to low solubility, many ECM proteins underrepresented previous proteomic datasets. Using an optimized three-step decellularization extraction method involving chaotrope digestion via hydroxylamine hydrochloride, we generated coverage the matrisome across 25 organs. We observe that top 100 most abundant from fractions all tissues are generally present tissues, indicating tissue matrices principally composed shared set proteins. However, these vary up 4000-fold between resulting highly unique profiles even with same primary A data reduction approach was used reveal related networks expressed varying basement membrane collagen subtypes.

Язык: Английский

Процитировано

34
Sex differences in vascular endothelial cells DOI Creative Commons
Jérôme Robert

Atherosclerosis, Год журнала: 2023, Номер 384, С. 117278 - 117278

Опубликована: Сен. 26, 2023

Endothelial cells are important constituents of blood vessels and play a critical role in vascular homeostasis. They do not only control the exchanges between surrounding tissues, but also essential regulating flow, modulating immune-cell trafficking controlling growth repair. dysfunction leads to cardiovascular diseases is characterized by deficiency secretion vasodilator molecules, elevated reactive oxygen species (ROS), expression adhesion molecules excretion proinflammatory cytokines. The sex hormones, estrogens, androgens progestogens, regulate endothelial functions. Because disease risk increases after menopause, it believed that female estrogens progestogens promote cell health function whereas androgens, male might be detrimental. However, as illustrated present review, picture simple. In addition, influences physiology independently hormones at genetic level.

Язык: Английский

Процитировано

30
Evaluation of the Interaction of Sex Hormones and Cardiovascular Function and Health DOI Creative Commons

Myrthe M. A. Willemars,

Miranda Nabben, Job A.J. Verdonschot

и другие.

Current Heart Failure Reports, Год журнала: 2022, Номер 19(4), С. 200 - 212

Опубликована: Май 28, 2022

Abstract Purpose of Review Sex hormones drive development and function reproductive organs or the secondary sex characteristics but their effects on cardiovascular system are poorly understood. In this review, we identify gaps in our understanding interaction between system. Recent Findings Studies progressively elucidating molecular functions specific cell types parallel with initiation crucial large randomized controlled trials aimed at improving therapies for diseases (CVDs) associated aberrant levels hormones. Summary contrast historical assumptions, now understand that men women show different symptoms progression CVDs. Abnormal pose an independent risk CVD, which is apparent conditions like Klinefelter syndrome, androgen insensitivity menopause. Moreover, hormone–based remain understudied may not be beneficial health.

Язык: Английский

Процитировано

38
Cardiac aging: from hallmarks to therapeutic opportunities DOI Creative Commons
Margaret H. Hastings, Qiulian Zhou, Chao Wu

и другие.

Cardiovascular Research, Год журнала: 2024, Номер unknown

Опубликована: Июнь 26, 2024

Abstract Cardiac ageing is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular, functional changes associated cardiac heart failure preserved ejection fraction (HFpEF). Key molecular mediators are considered within framework of established hallmarks ageing, particular attention to promising therapeutic candidates. We further delineate differential impacts structure function in men women, addressing hormonal chromosomal influences. The protective mitigating effects exercise HFpEF discussed, as inspiration for identification pathways that mitigate biological ageing. also emphasize how much remains be learned importance these efforts enhancing health populations worldwide.

Язык: Английский

Процитировано

7
Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and Research Implications DOI Open Access
Emily S. Lau, Aleksandra Binek, Sarah J. Parker

и другие.

Circulation Research, Год журнала: 2022, Номер 130(4), С. 578 - 592

Опубликована: Фев. 17, 2022

Sex-based differences in cardiovascular disease presentation, diagnosis, and response to therapies are well established, but mechanistic understanding translation clinical applications limited. Blood-based biomarkers have become an important tool for interrogating biologic pathways. Understanding sexual dimorphism the relationship between will enhance our insights into pathogenesis women, with potential translate improved individualized care men women or at risk disease. In this review, we examine how sex associates differential levels of blood-based influences effect on outcomes. We further summarize key along central pathways, including myocardial stretch/injury, inflammation, adipose tissue metabolism, fibrosis pathways versus women. Finally, present recommendations leveraging current knowledge future research innovation.

Язык: Английский

Процитировано

29
CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart DOI Open Access
Zachary L. Robbe, Wei Shi, Lauren K. Wasson

и другие.

Genes & Development, Год журнала: 2022, Номер 36(7-8), С. 468 - 482

Опубликована: Апрель 1, 2022

The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin complexes that mediates gene repression. NuRD essential for numerous developmental events, including heart development. Clinical genetic studies have provided direct evidence role chromodomain helicase DNA-binding protein 4 (CHD4), catalytic component NuRD, in congenital disease (CHD), atrial ventricular septal defects. Furthermore, it has been demonstrated CHD4 mammalian cardiomyocyte formation function. A key unresolved question how CHD4/NuRD localized to specific cardiac target genes, as neither nor can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses demonstrate interacts core transcription factors GATA4, NKX2-5, TBX5 during embryonic Using transcriptomics genome-wide occupancy data, characterized genomic landscape repression defined targets GATA4–CHD4, NKX2-5–CHD4, TBX5-CHD4 complexes. These data were used identify putative cis -regulatory elements controlled by these We genetically interrogated two silencers vivo: Acta1 Myh11 . show deletion leads inappropriate skeletal smooth muscle misexpression, respectively, heart. results delineate loci explicates mutations broadly expressed lead cardiac-specific states.

Язык: Английский

Процитировано

28