Salt Sensitivity of Blood Pressure.

The year 2024 marks the centennial of the initiation of the American Heart Association. Over the past 100 years, the American Heart Association has led groundbreaking discoveries in cardiovascular disease including salt sensitivity of blood pressure, which has been studied since the mid-1900s. Salt sensitivity of blood pressure is an important risk factor for cardiovascular events, but the phenotype remains unclear because of insufficient understanding of the underlying mechanisms and lack of feasible diagnostic tools. In honor of this centennial, we commemorate the initial discovery of salt sensitivity of blood pressure and chronicle the subsequent scientific discoveries and efforts to mitigate salt-induced cardiovascular disease with American Heart Association leading the way. We also highlight determinants of the pathophysiology of salt sensitivity of blood pressure in humans and recent developments in diagnostic methods and future prospects.

Integrated grade-wise profiling analysis reveals potential plasma miR-373-3p as prognostic indicator in Prostate Cancer & its target KPNA2.

Background: Plasma microRNAs (miRNAs) have recently garnered attention for their potential as stable biomarkers in the context of Prostate Cancer (PCa), demonstrating established associations with tumor grade, biochemical recurrence (BCR), and metastasis. This study seeks to assess the utility of plasma miRNAs as prognostic indicators for distinguishing between high-grade and low-grade PCa, and to explore their involvement in PCa pathogenesis. Methodology: We conducted miRNA profiling in both plasma and tissue specimens from patients with varying PCa grades. Subsequently, the identified miRNAs were validated in a substantial independent PCa cohort. Furthermore, we identified and confirmed the gene targets of these selected miRNAs through Western blot analysis. Results: In our plasma profiling investigation, we identified 98, 132, and 154 differentially expressed miRNAs (DEMs) in high-grade PCa vs. benign prostatic hyperplasia (BPH), low-grade PCa vs. BPH, and high-grade PCa vs. low-grade PCa, respectively. Our tissue profiling study revealed 111, 132, and 257 statistically significant DEMs for the same comparisons. Notably, miR-373-3p emerged as the sole consistently dysregulated miRNA in both plasma and tissue samples of PCa. This miRNA displayed significant overexpression in plasma and tissue samples, with fold changes of 3.584 ± 0.5638 and 8.796 ± 1.245, respectively. Furthermore, we observed a significant reduction in KPNA2 protein expression in PCa. Conclusion: Our findings lend support to the potential of plasma miR-373-3p as a valuable biomarker for predicting and diagnosing PCa. Additionally, this miRNA may contribute to the progression of PCa by inhibiting KPNA2 expression, shedding light on its role in the disease.

Exercise to Prevent Accelerated Vascular Aging in People Living With HIV.

Given advances in antiretroviral therapy, the mortality rate for HIV infection has dropped considerably over recent decades. However, people living with HIV (PLWH) experience longer life spans coupled with persistent immune activation despite viral suppression and potential toxicity from long-term antiretroviral therapy use. Consequently, PLWH face a cardiovascular disease (CVD) risk more than twice that of the general population, making it the leading cause of death among this group. Here, we briefly review the epidemiology of CVD in PLWH highlighting disparities at the intersections of sex and gender, age, race/ethnicity, and the contributions of social determinants of health and psychosocial stress to increased CVD risk among individuals with marginalized identities. We then overview the pathophysiology of HIV and discuss the primary factors implicated as contributors to CVD risk among PLWH on antiretroviral therapy. Subsequently, we highlight the functional evidence of premature vascular dysfunction as an early pathophysiological determinant of CVD risk among PLWH, discuss several mechanisms underlying premature vascular dysfunction in PLWH, and synthesize current research on the pathophysiological mechanisms underlying accelerated vascular aging in PLWH, focusing on immune activation, chronic inflammation, and oxidative stress. We consider understudied aspects such as HIV-related changes to the gut microbiome and psychosocial stress, which may serve as mechanisms through which exercise can abrogate accelerated vascular aging. Emphasizing the significance of exercise, we review various modalities and their impacts on vascular health, proposing a holistic approach to managing CVD risks in PLWH. The discussion extends to critical future study areas related to vascular aging, CVD, and the efficacy of exercise interventions, with a call for more inclusive research that considers the diversity of the PLWH population.

HIV-Associated Hypertension: Risks, Mechanisms, and Knowledge Gaps.

HIV type 1 (HIV-1) is the causative agent of AIDS. Since the start of the epidemic, HIV/AIDS has been responsible for ≈40 million deaths. Additionally, an estimated 39 million people are currently infected with the virus. HIV-1 primarily infects immune cells, such as CD4+ (cluster of differentiation 4+) T lymphocytes (T cells), and as a consequence, the number of CD4+ T cells progressively declines in people living with HIV. Within a span of ≈10 years, HIV-1 infection leads to the systemic failure of the immune system and progression to AIDS. Fortunately, potent antiviral therapy effectively controls HIV-1 infection and prevents AIDS-related deaths. The efficacy of the current antiviral therapy regimens has transformed the outcome of HIV/AIDS from a death sentence to a chronic disease with a prolonged lifespan of people living with HIV. However, antiviral therapy is not curative, is challenged by virus resistance, can be toxic, and, most importantly, requires lifelong adherence. Furthermore, the improved lifespan has resulted in an increased incidence of non-AIDS-related morbidities in people living with HIV including cardiovascular diseases, renal disease, liver disease, bone disease, cancer, and neurological conditions. In this review, we summarize the current state of knowledge of the cardiovascular comorbidities associated with HIV-1 infection, with a particular focus on hypertension. We also discuss the potential mechanisms known to drive HIV-1-associated hypertension and the knowledge gaps in our understanding of this comorbid condition. Finally, we suggest several directions of future research to better understand the factors, pathways, and mechanisms underlying HIV-1-associated hypertension in the post-antiviral therapy era.

A review of undergraduate research programs aimed at underrepresented students.

It is well-understood that the science, technology, engineering, and mathematics (STEM) fields have unique challenges that discourage recruiting and retaining underrepresented minorities. Research programs aimed at undergraduates have arisen as a critical mechanism for fostering innovation and addressing the challenges faced by underrepresented minorities. Here, we review various undergraduate research programs designed to provide exposure to undergraduates, with a focus on underrepresented minorities in STEM disciplines. We provide insight into selected programs' objectives, key features, potential limitations, and outcomes. We also offer recommendations for future improvements of each research program, particularly in the context of mentorship. These programs range from broad-reaching initiatives (e.g., Leadership Alliance) to more specific programs targeting underrepresented students. By offering a nuanced understanding of each program's structure, we seek to provide a brief overview of the landscape of diversity-focused STEM initiatives and a guide on how to run a research program effectively.

The graduate school guide: How to prepare for the qualifying exam and assemble a thesis/graduate committee.

Qualifying exams and thesis committees are crucial components of a PhD candidate's journey. However, many candidates have trouble navigating these milestones and knowing what to expect. This article provides advice on meeting the requirements of the qualifying exam, understanding its format and components, choosing effective preparation strategies, retaking the qualifying exam, if necessary, and selecting a thesis committee, all while maintaining one's mental health. This comprehensive guide addresses components of the graduate school process that are often neglected.

Influence of Proteolytic Cleavage of ENaC's Gamma Subunit upon Na+ and K+ Handling.

The ENaC γ subunit is essential for homeostasis of Na+, K+, and body fluid. Dual γ subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (PO), in vitro. Cleavage proximal to the tract occurs at a furin recognition sequence (143RKRR146, in the mouse γ subunit). Loss of furin-mediated cleavage prevents in vitro activation of the channel by proteolysis at distal sites. We hypothesized that 143RKRR146 mutation to 143QQQQ146 (γQ4) in 129/Sv mice would reduce ENaC PO, impair flow-stimulated flux of Na+ (JNa) and K+ (JK) in perfused collecting ducts, reduce colonic amiloride-sensitive short circuit current (ISC), and impair Na+, K+, and body fluid homeostasis. Immunoblot of γQ4/Q4 mouse kidney lysates confirmed loss of a band consistent in size with the furin-cleaved proteolytic fragment. However, γQ4/Q4 male mice on a low Na+ diet did not exhibit altered ENaC PO or flow-induced JNa, though flow-induced JK modestly decreased. Colonic amiloride-sensitive ISC in γQ4/Q4 mice was not altered. γQ4/Q4 males, but not females, exhibited mildly impaired fluid volume conservation when challenged with a low Na+ diet. Blood Na+ and K+ were unchanged on a regular, low Na+, or high K+ diet. These findings suggest that biochemical evidence of γ subunit cleavage should be used in isolation to evaluate ENaC activity. Further, factors independent of γ subunit cleavage modulate channel PO and the influence of ENaC on Na+, K+, and fluid volume homeostasis in 129/Sv mice, in vivo.

Endoplasmic Reticulum Stress in Hypertension and Salt Sensitivity of Blood Pressure.

PURPOSE OF REVIEW: Hypertension is a principal risk factor for cardiovascular morbidity and mortality, with its severity exacerbated by high sodium intake, particularly in individuals with salt-sensitive blood pressure. However, the mechanisms underlying hypertension and salt sensitivity are only partly understood. Herein, we review potential interactions in hypertension pathophysiology involving the immune system, endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and proteostasis pathways; identify knowledge gaps; and discuss future directions. RECENT FINDINGS: Recent advancements by our research group and others reveal interactions within and between adaptive and innate immune responses in hypertension pathophysiology. The salt-immune-hypertension axis is further supported by the discovery of the role of dendritic cells in hypertension, marked by isolevuglandin (IsoLG) formation. Alongside these broadened understandings of immune-mediated salt sensitivity, the contributions of T cells to hypertension have been recently challenged by groups whose findings did not support increased resistance of Rag-1-deficient mice to Ang II infusion. Hypertension has also been linked to ER stress and the UPR. Notably, a holistic approach is needed because the UPR engages in crosstalk with autophagy, the ubiquitin proteasome, and other proteostasis pathways, that may all involve hypertension. There is a critical need for studies to establish cause and effect relationships between ER stress and the UPR in hypertension pathophysiology in humans and to determine whether the immune system and ER stress function mainly to exacerbate or initiate hypertension and target organ injury. This review of recent studies proposes new avenues for future research for targeted therapeutic interventions.

Neuroimmunology of Cardiovascular Disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a leading cause of death and chronic disability worldwide. Yet, despite extensive intervention strategies the number of persons affected by CVD continues to rise. Thus, there is great interest in unveiling novel mechanisms that may lead to new treatments. Considering this dilemma, recent focus has turned to the neuroimmune mechanisms involved in CVD pathology leading to a deeper understanding of the brain's involvement in disease pathology. This review provides an overview of new and salient findings regarding the neuroimmune mechanisms that contribute to CVD. RECENT FINDINGS: The brain contains neuroimmune niches comprised of glia in the parenchyma and immune cells at the brain's borders, and there is strong evidence that these neuroimmune niches are important in both health and disease. Mechanistic studies suggest that the activation of glia and immune cells in these niches modulates CVD progression in hypertension and heart failure and contributes to the inevitable end-organ damage to the brain. This review provides evidence supporting the role of neuroimmune niches in CVD progression. However, additional research is needed to understand the effects of prolonged neuroimmune activation on brain function.

NETosis Drives Blood Pressure Elevation and Vascular Dysfunction in Hypertension.

BACKGROUND: Neutrophil extracellular traps (NETs) are composed of DNA, enzymes, and citrullinated histones that are expelled by neutrophils in the process of NETosis. NETs accumulate in the aorta and kidneys in hypertension. PAD4 (protein-arginine deiminase-4) is a calcium-dependent enzyme that is essential for NETosis. TRPV4 (transient receptor potential cation channel subfamily V member 4) is a mechanosensitive calcium channel expressed in neutrophils. Thus, we hypothesize that NETosis contributes to hypertension via NET-mediated endothelial cell (EC) dysfunction. METHODS: NETosis-deficient Padi4-/- mice were treated with Ang II (angiotensin II). Blood pressure was measured by radiotelemetry, and vascular reactivity was measured with wire myography. Neutrophils were cultured with or without ECs and exposed to normotensive or hypertensive uniaxial stretch. NETosis was measured by flow cytometry. ECs were treated with citrullinated histone H3, and gene expression was measured by quantitative reverse transcription PCR. Aortic rings were incubated with citrullinated histone H3, and wire myography was performed to evaluate EC function. Neutrophils were treated with the TRPV4 agonist GSK1016790A. Calcium influx was measured using Fluo-4 dye, and NETosis was measured by immunofluorescence. RESULTS: Padi4-/- mice exhibited attenuated hypertension, reduced aortic inflammation, and improved EC-dependent vascular relaxation in response to Ang II. Coculture of neutrophils with ECs and exposure to hypertensive uniaxial stretch increased NETosis and accumulation of neutrophil citrullinated histone H3. Histone H3 and citrullinated histone H3 exposure attenuates EC-dependent vascular relaxation. Treatment of neutrophils with the TRPV4 agonist GSK1016790A increases intracellular calcium and NETosis. CONCLUSIONS: These observations identify a role of NETosis in the pathogenesis of hypertension. Moreover, they define an important role of EC stretch and TRPV4 as initiators of NETosis. Finally, they define a role of citrullinated histones as drivers of EC dysfunction in hypertension.

Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV.

Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic anemia in HIV are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation of erythropoietin production, and persistent immune activation. Chronic inflammation from HIV infection adversely affects erythropoiesis, erythrocyte lifespan, and erythropoietin response, leading to a heightened risk of co-infections such as tuberculosis, persistent severe anemia, and increased mortality. Additionally, chronic anemia exacerbates the progression of HIV-associated nephrotoxicity and contributes to cardiovascular risk through immune activation and inflammation. This review highlights the cardinal role of chronic inflammation as a link connecting persistent anemia and cardiovascular complications in PLWH, emphasizing the need for a universal understanding of these interconnected pathways for targeted interventions.

Strategies for inducing and validating zinc deficiency and zinc repletion.

Given the growing interest in the role of zinc in the onset and progression of diseases, there is a crucial demand for reliable methods to modulate zinc homeostasis. Using a dietary approach, we provide validated strategies to alter whole-body zinc in mice, applicable across species. For confirmation of zinc status, animal growth rates as well as plasma and urine zinc levels were evaluated. The accessible and cost-effective methodology outlined will increase scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of diseases.NEW & NOTEWORTHY This methods paper details dietary approaches to alter zinc homeostasis in rodents and qualitative and quantitative methods to ensure the zinc status of experimental animals. The outlined accessible and cost-effective protocol will elevate scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of a multitude of health conditions and diseases.

Strategies for Inducing and Validating Zinc Deficiency and Zinc Repletion.

Given the growing interest in the role of zinc in the onset and progression of diseases, there is a crucial demand for reliable methods to modulate zinc homeostasis. Using a dietary approach, we provide validated strategies to alter whole-body zinc in mice, applicable across species. For confirmation of zinc status, animal growth rates as well as plasma and urine zinc levels were evaluated. The accessible and cost-effective methodology outlined will increase scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of diseases.

Reimagining bioRxiv and preprint servers as platforms for academic learning.

A popular preprint server, bioRxiv, is important as a tool for increased visibility for life science research. If used properly, however, bioRxiv can also be an important tool for training, as it may expose trainees (degree-seeking students undertaking research or internships directly related to their field of study) to the peer review process. Here, we offer a comprehensive guide to using bioRxiv as a training tool, as well as offer suggestions for improvements in bioRxiv, including confusion that may be caused by bioRxiv articles appearing on PubMed.

Running a successful STEMM summer program: A week-by-week guide.

While some established undergraduate summer programs are effective across many institutions, these programs may only be available to some principal investigators or may not fully address the diverse needs of incoming undergraduates. This article outlines a 10-week science, technology, engineering, mathematics, and medicine (STEMM) education program designed to prepare undergraduate students for graduate school through a unique model incorporating mentoring dyads and triads, cultural exchanges, and diverse activities while emphasizing critical thinking, research skills, and cultural sensitivity. Specifically, we offer a straightforward and adaptable guide that we have used for mentoring undergraduate students in a laboratory focused on mitochondria and microscopy, but which may be customized for other disciplines. Key components include self-guided projects, journal clubs, various weekly activities such as mindfulness training and laboratory techniques, and a focus on individual and cultural expression. Beyond this unique format, this 10-week program also seeks to offer an intensive research program that emulates graduate-level experiences, offering an immersive environment for personal and professional development, which has led to numerous achievements for past students, including publications and award-winning posters.

Erythrocyte glycocalyx sensitivity to sodium is associated with salt sensitivity of blood pressure in women but not men.

Background: While salt sensitivity of blood pressure (SSBP) is a risk factor for hypertension, end-organ damage and death, most studies are conducted in western countries and in White people. We previously found that the prevalence of SSBP in Blacks living in Sub-Saharan Africa is as high as 75-80% like what has been reported in the west. Erythrocyte glycocalyx sensitivity to sodium (eGCSS), a marker of sodium-induced damage to the erythrocyte and vascular endothelial glycocalyx is thought to be related to blood pressure perturbations associated with salt intake. We hypothesized that SSBP correlates with eGCSS differently in men and women in Black people. Methods: We conducted a cross sectional study using data from our recent clinical trial from Livingstone University Teaching Hospital among 117 normotensive young adults. We used a "salt blood test" to determine eGCSS and an immediate pressor response to oral salt (IPROS) for the diagnosis of SSBP. Results: The proportion of males were equal to females and the median age (interquartile range) of the participants was 29 (22-45) years. The eGCSS scores were higher in salt-resistant females compared to salt-sensitive females and males. eGCSS correlated negatively with SSBP (AOR 0.98, 95% CI 0.97-0.99, p = 0.008), however, this relationship was driven by female sex and abrogated by male sex. Although blood pressure elevations exhibited a sustained bimodal pattern in both sexes, in males, systolic and diastolic blood pressure never returned to baseline during the time course as it did in females. Conclusion: In this study, eGCSS correlated negatively with SSBP in black women but not in black men and the pressor response to dietary salt was significantly higher in men compared to women. These results suggest that women tend to have a higher disruption of the vascular endothelial glycocalyx by an acute salt load, implying that acute changes in blood pressure may not be driven directly by the endothelial glycocalyx. Our findings suggest a novel mechanism linking eGCSS and SSBP with potential implications for sex differences in salt-induced cardiovascular disease.Clinical trial registration: https://clinicaltrials.gov/, identifier [NCT04844255].

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

AIMS: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signaling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and hematologic disorders including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are a major component of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. METHODS AND RESULTS: Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared to WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, proarrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodeling in vitro. Inhibition of soluble TNF-α prevented electrical remodeling and AF susceptibility, while IL-1ß inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. CONCLUSIONS: These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and in humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the proarrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodeling.

Hypertension Related Co-Morbidities and Complications in Women of Sub-Saharan Africa: A Brief Review.

Hypertension is the leading cause of cardiovascular disease in women, and sub-Saharan African (SSA) countries have some of the highest rates of hypertension in the world. Expanding knowledge of causes, management, and awareness of hypertension and its co-morbidities worldwide is an effective strategy to mitigate its harms, decrease morbidities and mortality, and improve individual quality of life. Hypertensive disorders of pregnancy (HDPs) are a particularly important subset of hypertension, as pregnancy is a major stress test of the cardiovascular system and can be the first instance in which cardiovascular disease is clinically apparent. In SSA, women experience a higher incidence of HDP compared with other African regions. However, the region has yet to adopt treatment and preventative strategies for HDP. This delay stems from insufficient awareness, lack of clinical screening for hypertension, and lack of prevention programs. In this brief literature review, we will address the long-term consequences of hypertension and HDP in women. We evaluate the effects of uncontrolled hypertension in SSA by including research on heart disease, stroke, kidney disease, peripheral arterial disease, and HDP. Limitations exist in the number of studies from SSA; therefore, we will use data from countries across the globe, comparing and contrasting approaches in similar and dissimilar populations. Our review highlights an urgent need to prioritize public health, clinical, and bench research to discover cost-effective preventative and treatment strategies that will improve the lives of women living with hypertension in SSA.

Mitochondria in disease: changes in shapes and dynamics.

Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.