Promoting a more diverse and inclusive research workforce through the research scholars program.

Background: Novel and comprehensive approaches are needed to address shortcomings in the diversity and inclusiveness of the scientific workforce. In response to this need and informed by multiple programs and data sources, we created the Research Scholars Program (RSP). The RSP is a yearlong program for early-career faculty with an overall objective to overcome barriers to the academic success, retention, progression, and promotion of groups underrepresented in biomedical and behavioral research.

Aortic Stress Activates an Adaptive Program in Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength and Protects Against Aneurysm and Dissection in Mice.

Background: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD).

Methods: We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion.

Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet.

Adipocyte-Derived Serum Amyloid A Promotes Angiotensin II-Induced Abdominal Aortic Aneurysms in Obese C57BL/6J Mice.

Background: Obesity increases the risk for human abdominal aortic aneurysms (AAAs) and enhances Ang II (angiotensin II)-induced AAA formation in C57BL/6J mice. Obesity is also associated with increases in perivascular fat that expresses proinflammatory markers including SAA (serum amyloid A). We previously reported that deficiency of SAA significantly reduces Ang II-induced inflammation and AAA in hyperlipidemic apoE-deficient mice.

Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-β Signaling.

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS ( = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients ( = 4). The expression of key molecules was confirmed by immunostaining.

Twenty Years of Studying AngII (Angiotensin II)-Induced Abdominal Aortic Pathologies in Mice: Continuing Questions and Challenges to Provide Insight Into the Human Disease.

AngII (angiotensin II) infusion in mice has been used to provide mechanistic insight into human abdominal aortic aneurysms for over 2 decades. This is a technically facile animal model that recapitulates multiple facets of the human disease. Although numerous publications have reported abdominal aortic aneurysms with AngII infusion in mice, there remain many fundamental unanswered questions such as uniformity of describing the pathological characteristics and which cell type is stimulated by AngII to promote abdominal aortic aneurysms.

SARS-CoV-2 Spike Protein Regulation of Angiotensin Converting Enzyme 2 and Tissue Renin-Angiotensin Systems: Influence of Biologic Sex.

Angiotensin converting enzyme 2 (ACE2) is an enzyme that limits activity of the renin-angiotensin system (RAS) and also serves as a receptor for the SARS-CoV-2 Spike (S) protein. Binding of S protein to ACE2 causes internalization which activates local RAS. ACE2 is on the X chromosome and its expression is regulated by sex hormones.

Therapeutic Assessment of Combination Therapy with a Neprilysin Inhibitor and Angiotensin Type 1 Receptor Antagonist on Angiotensin II-Induced Atherosclerosis, Abdominal Aortic Aneurysms, and Hypertension.

Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis, and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system.

Monosomy X in Female Mice Influences the Regional Formation and Augments the Severity of Angiotensin II-Induced Aortopathies.

Objective: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II-induced aortopathies.

Single-Cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue.

Background: Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we aimed to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues.

Methods: We performed single-cell RNA sequencing analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 control subjects (2 women and 1 man).

Two Amino Acids Proximate to the Renin Cleavage Site of Human Angiotensinogen Do Not Affect Blood Pressure and Atherosclerosis in Mice-Brief Report.

Objective: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT) mice in an LDL receptor-deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]).

Aortic Aneurysms and Dissections Series: Part II: Dynamic Signaling Responses in Aortic Aneurysms and Dissections.

Aortic structure and function are controlled by the coordinated actions of different aortic cells and the extracellular matrix. Several pathways have been identified that control the aortic wall in a cell-type-specific manner and play diverse roles in various phases of aortic injury, repair, and remodeling. This complexity of signaling in the aortic wall poses challenges to the development of therapeutic strategies for treating aortic aneurysms and dissections.

Aortic Aneurysms and Dissections Series.

The aortic wall is composed of highly dynamic cell populations and extracellular matrix. In response to changes in the biomechanical environment, aortic cells and extracellular matrix modulate their structure and functions to increase aortic wall strength and meet the hemodynamic demand. Compromise in the structural and functional integrity of aortic components leads to aortic degeneration, biomechanical failure, and the development of aortic aneurysms and dissections (AAD).

Female Mice Exposed to Postnatal Neglect Display Angiotensin II-Dependent Obesity-Induced Hypertension.

Background We have previously reported that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show exacerbated diet-induced obesity associated with hypertension. The goal of this study was to test whether MSEW promotes angiotensin II-dependent hypertension via activation of the renin-angiotensin system in adipose tissue. Methods and Results MSEW was achieved by daily separations from the dam and weaning at postnatal day 17, while normally reared controls were weaned at postnatal day 21.

The Value of Innovation to Implementation Program (VIP): A strategic approach to aligning and leveraging academic research and clinical care missions.

Problem: Inefficient implementation of evidence-based care garners increasing attention as a source of suboptimal value of clinical care, and integration of quality improvement methodology into clinical practice represents a potential solution. Academic medical centers (AMCs) often have expertise in implementation science, yet it is not leveraged effectively to solve operational inefficiencies or to rapidly implement evidence-based practices (EBPs).

Approach: To leverage in-house research expertise, the University of Kentucky (UK) College of Medicine and Center for Health Services Research (CHSR) launched a pilot awards program-Value of Innovation to Implementation Program (VIP)-across its health system and six health professional colleges.

Costs of Implementing Quality in Research Practice.

Using standardized guidelines in preclinical research has received increased interest in light of recent concerns about transparency in data reporting and apparent variation in data quality, as evidenced by irreproducibility of results. Although the costs associated with supporting quality through a quality management system are often obvious line items in laboratory budgets, the treatment of the costs associated with quality failure is often overlooked and difficult to quantify. Thus, general estimations of quality costs can be misleading and inaccurate, effectively undervaluing costs recovered by reducing quality defects.

Adipocyte deficiency of ACE2 increases systolic blood pressures of obese female C57BL/6 mice.

Background: Obesity increases the risk for hypertension in both sexes, but the prevalence of hypertension is lower in females than in males until menopause, despite a higher prevalence of obesity in females. We previously demonstrated that angiotensin-converting enzyme 2 (ACE2), which cleaves the vasoconstrictor, angiotensin II (AngII), to generate the vasodilator, angiotensin-(1-7) (Ang-(1-7)), contributes to sex differences in obesity-hypertension. ACE2 expression in adipose tissue was influenced by obesity in a sex-specific manner, with elevated ACE2 expression in obese female mice.

Effects of Aryl Hydrocarbon Receptor Deficiency on PCB-77-Induced Impairment of Glucose Homeostasis during Weight Loss in Male and Female Obese Mice.

Background: Lipophilic polychlorinated biphenyls (PCBs) accumulate with obesity, but during weight loss, liberated PCBs act as ligands of the aryl hydrocarbon receptor (AhR) to negatively influence health. Previous studies demonstrated that PCB-77 administration to obese male mice impaired glucose tolerance during weight loss. Recent studies indicate higher toxic equivalencies of dioxin-like PCBs in exposed females than males.

XX sex chromosome complement promotes atherosclerosis in mice.

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown.

Pseudomonas aeruginosa-derived pyocyanin reduces adipocyte differentiation, body weight, and fat mass as mechanisms contributing to septic cachexia.

Pseudomonas aeruginosa, a leading cause of sepsis, produces pyocyanin, a blue-pigmented virulence factor. Sepsis is associated with cachexia, but mechanisms are unknown and conventional nutrition approaches are not effective treatments. Pyocyanin has affinity for the aryl hydrocarbon receptor (AhR), which is expressed on adipocytes and regulates adipocyte differentiation.

Pancreatic AT1aR Deficiency Decreases Insulin Secretion in Obese C57BL/6 Mice.

Background: Previously, we demonstrated that obese mice have marked elevations in systemic concentrations of angiotensin II (AngII). Drugs that inhibit the renin-angiotensin system (RAS), including angiotensin type 1 receptor (AT1R) antagonists, have been reported to delay the onset of type 2 diabetes (T2D), suggesting improvements in insulin sensitivity or regulation of pancreatic insulin secretion. Pancreatic islets possess components of the RAS, including AT1R, but it is unclear if AngII acts at islets to regulate insulin secretion during the development of T2D.