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Article: An Introduction to Epigenetics in Cardiovascular Development, Disease, and Sexualization.

Cunningham, Christine M / Eghbali, Mansoureh

Advances in experimental medicine and biology

2018 Volume 1065, Page(s) 31–47

Abstract: Epigenetic regulation of gene expression is integral to cell differentiation, development, and disease. Modes of epigenetic regulation-including DNA methylation, histone modifications, and ncRNA-based regulation-alter chromatin structure, promotor ... ...

Abstract	Epigenetic regulation of gene expression is integral to cell differentiation, development, and disease. Modes of epigenetic regulation-including DNA methylation, histone modifications, and ncRNA-based regulation-alter chromatin structure, promotor accessibility, and contribute to posttranscriptional modifications. In the cardiovascular system, epigenetic regulation is necessary for proper cardiovascular development and homeostasis, while epigenetic dysfunction is associated with improper cardiac development and disease.Early sexualization of tissues, including X-inactivation in females and maternal and paternal imprinting, is also orchestrated through epigenetic mechanisms. Furthermore, sex chromosomes encode various sex-specific genes involved in epigenetic regulation, while sex hormones can act as regulatory cofactors that may predispose or protect males and females against developing diseases with a marked sex bias.The following book chapter summarizes the field of epigenetics in the context of cardiovascular development and disease while also highlighting the role of epigenetic regulation as a powerful source of sex differences within the cardiovascular system.
MeSH term(s)	Animals ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/genetics ; Chromosomes, Human, X ; Chromosomes, Human, Y ; Epigenesis, Genetic ; Female ; Genetic Predisposition to Disease ; Genomic Imprinting ; Health Status Disparities ; Humans ; Male ; Phenotype ; Risk Factors ; Sex Characteristics ; Sex Factors ; X Chromosome Inactivation
Language	English
Publishing date	2018-08-02
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-77932-4_2
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Article ; Online: Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

Zhao, Lan / Cunningham, Christine M / Andruska, Adam M / Schimmel, Katharina / Ali, Md Khadem / Kim, Dongeon / Gu, Shenbiao / Chang, Jason L / Spiekerkoetter, Edda / Nicolls, Mark R

Lab animal

2024 Volume 53, Issue 2, Page(s) 43–55

Abstract: The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of ... ...

Abstract	The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement.
MeSH term(s)	Humans ; Rats ; Animals ; Bacteria ; Lactobacillales ; Lung/microbiology ; Microbiota/genetics
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ISSN	1548-4475
ISSN (online)	1548-4475
DOI	10.1038/s41684-023-01322-x
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Article: Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

Zhao, Lan / Cunningham, Christine M / Andruska, Adam M / Schimmel, Katharina / Ali, Md Khadem / Kim, Dongeon / Gu, Shenbiao / Chang, Jason L / Spiekerkoetter, Edda / Nicolls, Mark R

bioRxiv : the preprint server for biology

2023

Abstract	The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearman's correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LAB's presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life.
Language	English
Publishing date	2023-05-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.19.541527
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Article ; Online: Y-Chromosome Gene,

Cunningham, Christine M / Li, Min / Ruffenach, Gregoire / Doshi, Mitali / Aryan, Laila / Hong, Jason / Park, John / Hrncir, Haley / Medzikovic, Lejla / Umar, Soban / Arnold, Arthur P / Eghbali, Mansoureh

American journal of respiratory and critical care medicine

2022 Volume 206, Issue 2, Page(s) 186–196

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Animals ; Chemokines/metabolism ; Disease Models, Animal ; Endothelial Cells/metabolism ; Familial Primary Pulmonary Hypertension/genetics ; Female ; Genes, Y-Linked ; Humans ; Hypertension, Pulmonary/genetics ; Hypoxia ; Male ; Mice ; Minor Histocompatibility Antigens/genetics ; Nuclear Proteins/genetics ; Pulmonary Artery ; Rats
Chemical Substances	Chemokines ; Minor Histocompatibility Antigens ; Nuclear Proteins ; UTY protein, human
Language	English
Publishing date	2022-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202110-2309OC
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Article ; Online: Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19.

Medzikovic, Lejla / Cunningham, Christine M / Li, Min / Amjedi, Marjan / Hong, Jason / Ruffenach, Gregoire / Eghbali, Mansoureh

Journal of molecular and cellular cardiology

2020 Volume 148, Page(s) 25–33

Abstract: The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, cardiovascular injury is reported to contribute to a ... ...

Abstract	The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, cardiovascular injury is reported to contribute to a substantial proportion of COVID-19 deaths. Preexisting cardiovascular disease (CVD) is among the most common risk factors for hospitalization and death in COVID-19 patients, and the pathogenic mechanisms of COVID-19 disease progression itself may promote the development of cardiovascular injury, increasing risk of in-hospital death. Sex differences in COVID-19 are becoming more apparent as mounting data indicate that males seem to be disproportionately at risk of severe COVID-19 outcome due to preexisting CVD and COVID-19-related cardiovascular injury. In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.
MeSH term(s)	Angiotensin-Converting Enzyme 2/genetics ; Arrhythmias, Cardiac/complications ; Arrhythmias, Cardiac/epidemiology ; COVID-19/complications ; COVID-19/epidemiology ; COVID-19/genetics ; Cardiovascular Diseases/complications ; Cardiovascular Diseases/epidemiology ; Disease Progression ; Disease Susceptibility ; Endothelium, Vascular/pathology ; Female ; Humans ; Inflammation ; Male ; Microcirculation ; Obesity/complications ; Risk Factors ; Sex Factors ; Smoking ; Thrombosis/complications ; Thrombosis/epidemiology
Chemical Substances	ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-08-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2020.08.007
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Article ; Online: The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.

Iorga, Andrea / Cunningham, Christine M / Moazeni, Shayan / Ruffenach, Gregoire / Umar, Soban / Eghbali, Mansoureh

Biology of sex differences

2017 Volume 8, Issue 1, Page(s) 33

Abstract: Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of ... ...

Abstract	Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.
MeSH term(s)	Animals ; Cardiovascular Agents/therapeutic use ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/metabolism ; Estrogens/metabolism ; Estrogens/therapeutic use ; Humans ; Receptors, Estrogen/metabolism
Chemical Substances	Cardiovascular Agents ; Estrogens ; Receptors, Estrogen
Language	English
Publishing date	2017-10-24
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2587352-0
ISSN	2042-6410 ; 2042-6410
ISSN (online)	2042-6410
ISSN	2042-6410
DOI	10.1186/s13293-017-0152-8
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Article ; Online: Effect of Anatomic Variability and Level of Approach on Perioperative Vascular Complications With Anterior Lumbar Interbody Fusion.

Nourian, Ardalan Alen / Cunningham, Christine M / Bagheri, Ali / Bruffey, James D / Eastlack, Robert K

Spine

2016 Volume 41, Issue 2, Page(s) E73–7

Abstract: Study design: Retrospective review of prospectively collected data.: Objective: The study aim was to determine the prevalence of vascular complications associated with anterior lumbar interbody fusion (ALIF) as a function of anatomic variation and ... ...

Abstract	Study design: Retrospective review of prospectively collected data. Objective: The study aim was to determine the prevalence of vascular complications associated with anterior lumbar interbody fusion (ALIF) as a function of anatomic variation and the number of levels fused. Summary of background data: ALIF often requires mobilization of the great vessels, particularly when exposing levels above L5-S1. The exposure can be more challenging in the setting of spondylolisthesis or transitional anatomy. Methods: This retrospective review of prospectively collected data from our spine database identified 204 patients who had undergone single level (n = 142) or multilevel (n = 62) ALIF from 2008 to 2013 with minimum 6-month follow-up. Average age was 58 years; 57% were female. Preoperative radiographic assessment for spondylolisthesis and transitional anatomy was performed. Body mass index, estimated blood loss, and levels of ALIF were recorded. Intraoperative vascular injury, postoperative deep venous thrombosis, and pulmonary embolism events were noted. Results: Eleven patients experienced postoperative thromboembolic events and were more likely to have had intraoperative vascular injury compared with patients who did not develop a vascular complication (36% and 5%, respectively; P = 0.004). Estimated blood loss was significantly higher in patients with spondylolisthesis when compared to patients without spondylolisthesis (520 cc vs. 103 cc, respectively; P = 0.017) or transitional anatomy (347 cc vs. 262 cc, respectively; P = 0.022). Patients undergoing multilevel ALIF had significantly higher blood loss than patients undergoing a single level procedure (684 cc vs. 107 cc; P < 0.001). Patient characteristics, blood loss, anatomic variation, and level of approach were not associated with the development of postoperative thromboembolic complications. Conclusion: Performing ALIF in the setting of spondylolisthesis or transitional anatomy resulted in higher blood loss. Patients undergoing multilevel rather than single level ALIF experienced greater blood loss. Because patients with intraoperative vascular injury had increased likelihood of postoperative thromboembolic event, thrombosis prophylaxis should be considered in these patients. Level of evidence: 4.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Blood Loss, Surgical ; Databases, Factual ; Female ; Humans ; Lumbar Vertebrae/abnormalities ; Lumbar Vertebrae/diagnostic imaging ; Lumbar Vertebrae/surgery ; Male ; Middle Aged ; Prevalence ; Pulmonary Embolism/diagnosis ; Pulmonary Embolism/epidemiology ; Radiography ; Retrospective Studies ; Risk Factors ; Spinal Fusion/adverse effects ; Spondylolisthesis/complications ; Spondylolisthesis/diagnosis ; Spondylolisthesis/surgery ; Time Factors ; Treatment Outcome ; Vascular System Injuries/diagnosis ; Vascular System Injuries/epidemiology ; Venous Thrombosis/diagnosis ; Venous Thrombosis/epidemiology ; Young Adult
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	752024-4
ISSN	1528-1159 ; 0362-2436
ISSN (online)	1528-1159
ISSN	0362-2436
DOI	10.1097/BRS.0000000000001160
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Article ; Online: Free Fatty Acid Receptor G-protein-coupled Receptor 40 Mediates Lipid Emulsion-induced Cardioprotection.

Umar, Soban / Li, Jingyuan / Hannabass, Kyle / Vaillancourt, Mylene / Cunningham, Christine M / Moazeni, Shayan / Mahajan, Aman / Eghbali, Mansoureh

Anesthesiology

2018 Volume 129, Issue 1, Page(s) 154–162

Abstract: Background: We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored ... ...

Abstract	Background: We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein-coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein-coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. Methods: Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein-coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg · min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV). Results: G-protein-coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product: 2,186 ± 1,783 [n = 7] vs. 11,607 ± 4,347 [n = 8]; left ventricular developed pressure: 22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = -443 ± 262 vs. -1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR: 302 ± 17 vs. 312 ± 38; ejection fraction: 69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%). Conclusions: G-protein-coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
MeSH term(s)	Animals ; Benzoates/pharmacology ; Cardiotonic Agents/pharmacology ; Cells, Cultured ; Fat Emulsions, Intravenous/pharmacology ; Isolated Heart Preparation/methods ; Male ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/physiology ; Pyrimidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/physiology
Chemical Substances	Benzoates ; Cardiotonic Agents ; Fat Emulsions, Intravenous ; Ffar1 protein, mouse ; GW1100 ; Pyrimidines ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2018-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	269-0
ISSN	1528-1175 ; 0003-3022
ISSN (online)	1528-1175
ISSN	0003-3022
DOI	10.1097/ALN.0000000000002195
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Article: Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19

Medzikovic, Lejla / Cunningham, Christine M / Li, Min / Amjedi, Marjan / Hong, Jason / Ruffenach, Gregoire / Eghbali, Mansoureh

J Mol Cell Cardiol

Abstract	The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, cardiovascular injury is reported to contribute to a substantial proportion of COVID-19 deaths. Preexisting cardiovascular disease (CVD) is among the most common risk factors for hospitalization and death in COVID-19 patients, and the pathogenic mechanisms of COVID-19 disease progression itself may promote the development of cardiovascular injury, increasing risk of in-hospital death. Sex differences in COVID-19 are becoming more apparent as mounting data indicate that males seem to be disproportionately at risk of severe COVID-19 outcome due to preexisting CVD and COVID-19-related cardiovascular injury. In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #726897
Database	COVID19

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Article ; Online: Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19.

Medzikovic, Lejla / Cunningham, Christine M / Li, Min / Amjedi, Marjan / Hong, Jason / Ruffenach, Gregoire / Eghbali, Mansoureh

2020

Abstract	The novel 2019 coronavirus disease (COVID-19), resulting from severe acute respiratory syndrome coronarvirus-2 (SARS-CoV-2) infection, typically leads to respiratory failure in severe cases; however, cardiovascular injury is reported to contribute to a substantial proportion of COVID-19 deaths. Preexisting cardiovascular disease (CVD) is among the most common risk factors for hospitalization and death in COVID-19 patients, and the pathogenic mechanisms of COVID-19 disease progression itself may promote the development of cardiovascular injury, increasing risk of in-hospital death. Sex differences in COVID-19 are becoming more apparent as mounting data indicate that males seem to be disproportionately at risk of severe COVID-19 outcome due to preexisting CVD and COVID-19-related cardiovascular injury. In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.
Keywords	ACE2 ; Arrhythmia ; COVID-19 ; Cardiovascular ; Sex differences ; Thrombosis ; Cardiovascular System & Hematology ; Cardiorespiratory Medicine and Haematology ; Medical Physiology ; covid19
Subject code	610
Publishing date	2020-08-22
Publisher	eScholarship, University of California
Publishing country	us
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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