BBSome: a New Player in Hypertension and Other Cardiovascular Risks

Cardiovascular Risks ◽

Cellular Processes ◽

Associated Proteins ◽

The BBSome is an octameric protein complex involved in Bardet-Biedl syndrome (BBS), a human pleiotropic, autosomal recessive condition. Patients with BBS display various clinical features including obesity, hypertension, and renal abnormalities. Association studies have also linked the BBS genes to hypertension and other cardiovascular risks in the general population. The BBSome was originally associated with the function of cilia, a highly specialized organelle that extend from the cell membrane of most vertebrate cells. However, subsequent studies have implicated the BBSome in the control of a myriad of other cellular processes not related to cilia including cell membrane localization of receptors and gene expression. The development of animal models of BBS such as mouse lines lacking various components of the BBSome and associated proteins has facilitated studying their role in the control of cardiovascular function and deciphering the pathophysiological mechanisms responsible for the cardiovascular aberrations associated with BBS. These studies revealed the importance of the neuronal, renal, vascular, and cardiac BBSome in the regulation of blood pressure, renal function, vascular reactivity, and cardiac development. The BBSome has also emerged as a critical regulator of key systems involved in cardiovascular control including the renin-angiotensin system. Better understanding of the influence of the BBSome on the molecular and physiological processes relevant to cardiovascular health and disease has the potential of identifying novel mechanisms underlying hypertension and other cardiovascular risks.

Opposing tissue-specific roles of angiotensin in the pathogenesis of obesity, and implications for obesity-related hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00224.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. R1463-R1473 ◽

Cited By ~ 16

Author(s):

Nicole K. Littlejohn ◽

Justin L. Grobe

Keyword(s):

Energy Balance ◽

Cardiovascular Health ◽

Control Mechanisms ◽

Signaling Mechanism ◽

Angiotensin System ◽

Tissue Specific ◽

Specific Effects ◽

Health And Disease ◽

Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and nonaerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue-specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity-mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-related hypertension.

Tracking the Antibody Immunome in Sporadic Colorectal Cancer by Using Antigen Self-Assembled Protein Arrays

Cancers ◽

10.3390/cancers13112718 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2718

Author(s):

María González-González ◽

José María Sayagués ◽

Luis Muñoz-Bellvís ◽

Carlos Eduardo Pedreira ◽

Marcello L. R. de Campos ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Utility ◽

Genetic Alterations ◽

Western World ◽

Sporadic Colorectal Cancer ◽

Protein Arrays ◽

Humoral Immune ◽

Cellular Processes ◽

Healthy Donors ◽

Associated Proteins

Sporadic Colorectal Cancer (sCRC) is the third leading cause of cancer death in the Western world, and the sCRC patients presenting with synchronic metastasis have the poorest prognosis. Genetic alterations accumulated in sCRC tumor cells translate into mutated proteins and/or abnormal protein expression levels, which contribute to the development of sCRC. Then, the tumor-associated proteins (TAAs) might induce the production of auto-antibodies (aAb) via humoral immune response. Here, Nucleic Acid Programmable Protein Arrays (NAPPArray) are employed to identify aAb in plasma samples from a set of 50 sCRC patients compared to seven healthy donors. Our goal was to establish a systematic workflow based on NAPPArray to define differential aAb profiles between healthy individuals and sCRC patients as well as between non-metastatic (n = 38) and metastatic (n = 12) sCRC, in order to gain insight into the role of the humoral immune system in controlling the development and progression of sCRC. Our results showed aAb profile based on 141 TAA including TAAs associated with biological cellular processes altered in genesis and progress of sCRC (e.g., FSCN1, VTI2 and RPS28) that discriminated healthy donors vs. sCRC patients. In addition, the potential capacity of discrimination (between non-metastatic vs. metastatic sCRC) of 7 TAAs (USP5, ML4, MARCKSL1, CKMT1B, HMOX2, VTI2, TP53) have been analyzed individually in an independent cohort of sCRC patients, where two of them (VTI2 and TP53) were validated (AUC ~75%). In turn, these findings provided novel insights into the immunome of sCRC, in combination with transcriptomics profiles and protein antigenicity characterizations, wich might lead to the identification of novel sCRC biomarkers that might be of clinical utility for early diagnosis of the tumor. These results explore the immunomic analysis as potent source for biomarkers with diagnostic and prognostic value in CRC. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these novel sCRC immunomic biomarkers.

Covisualization by computation optical-sectioning microscopy of integrin and associated proteins at the cell membrane of living onion protoplasts

PROTOPLASMA ◽

10.1007/bf01882029 ◽

1996 ◽

Vol 194 (3-4) ◽

pp. 215-230 ◽

Cited By ~ 45

Author(s):

J. Scott Gens ◽

Christophe Reuzeau ◽

Keith W. Doolittle ◽

James G. McNally ◽

Barbara G. Pickard

Keyword(s):

Cell Membrane ◽

Optical Sectioning ◽

Associated Proteins

Association between Hypomagnesemia, COVID-19, Respiratory Tract and Lung Disease

The Open Respiratory Medicine Journal ◽

10.2174/1874306402115010043 ◽

2021 ◽

Vol 15 (1) ◽

pp. 43-45

Author(s):

Gavino Faa ◽

Luca Saba ◽

Daniela Fanni ◽

Goce Kalcev ◽

Mauro Carta

Keyword(s):

Risk Category ◽

Controlled Trials ◽

Type I ◽

Magnesium Supplementation ◽

Angiotensin System ◽

Old Adults ◽

Cd8 T Lymphocytes ◽

High Risk Category ◽

The complexity of COVID-19 is also related to the multiple molecular pathways triggered by SARS-CoV-2, which is able to cause type I pneumocyte death, trigger intravascular coagulation, interfere with the renin-angiotensin system, dysregulate iron metabolism, ending with the insurgence of a cytokine storm which may lead to death. Old adults with obesity, hypertension, and diabetes are among the high-risk category groups more prone to SARS-CoV-2 infection. Magnesium has been reported to play a major role both in physiology and in pathology, particularly in elderly people, regulating cytotoxic functions of natural killer (NK) cells and CD8+ T lymphocytes. In spite of the absence of controlled trials, the possibility of magnesium supplementation for supportive treatment in patients with COVID-19 should be encouraged. This could be useful in all phases of the COVID-19 disease.

Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.646901 ◽

2021 ◽

Vol 13 ◽

Author(s):

David Vogrinc ◽

Katja Goričar ◽

Vita Dolžan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Age Of Onset ◽

Association Studies ◽

The Elderly ◽

Gene Clustering ◽

Molecular Pathways ◽

Genome Wide Association Studies ◽

Cellular Processes ◽

Increased Risk

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.

Deformation Measurements of Neuronal Excitability Using Incoherent Holography Lattice Light-Sheet Microscopy (IHLLS)

Photonics ◽

10.3390/photonics8090383 ◽

2021 ◽

Vol 8 (9) ◽

pp. 383

Author(s):

Mariana Potcoava ◽

Jonathan Art ◽

Simon Alford ◽

Christopher Mann

Keyword(s):

Cell Membrane ◽

Structural Changes ◽

Neuronal Excitability ◽

Light Sheet ◽

Phase Imaging ◽

Excitable Cells ◽

Full Field ◽

Cellular Processes ◽

Light Sheet Microscopy ◽

Fluorescent Markers

Stimuli to excitable cells and various cellular processes can cause cell surface deformations; for example, when excitable cell membrane potentials are altered during action potentials. However, these cellular changes may be at or below the diffraction limit (in dendrites the structures measured are as small as 1 µm), and imaging by traditional methods is challenging. Using dual lenses incoherent holography lattice light-sheet (IHLLS-2L) detection with holographic phase imaging of selective fluorescent markers, we can extract the full-field cellular morphology or structural changes of the object’s phase in response to external stimulus. This approach will open many new possibilities in imaging neuronal activity and, overall, in light sheet imaging. In this paper, we present IHLLS-2L as a well-suited technique for quantifying cell membrane deformation in neurons without the actuation of a sample stage or detection microscope objective.

Gene variants of the renin–angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

Clinical Science ◽

10.1042/cs20090498 ◽

2010 ◽

Vol 118 (8) ◽

pp. 487-506 ◽

Cited By ~ 10

Author(s):

Gavin R. Norton ◽

Richard Brooksbank ◽

Angela J. Woodiwiss

Keyword(s):

Association Studies ◽

Large Population ◽

Human Populations ◽

Incomplete Penetrance ◽

Gene Variants ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Genes ◽

The Impact

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin–angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of ‘incomplete penetrance’ through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating ‘haplotypes’.

Abstract 053: Association Of Pre-pregnancy Cardiovascular Health With Adverse Maternal And Fetal Outcomes

Circulation ◽

10.1161/circ.143.suppl_1.053 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Michael C Wang ◽

Priya M Freaney ◽

Amanda M Perak ◽

Norrina B Allen ◽

Philip Greenland ◽

...

Keyword(s):

Low Birthweight ◽

Cardiovascular Health ◽

Fetal Death ◽

Cross Sectional Study ◽

Fetal Outcomes ◽

Pregnancy Risk ◽

Cross Sectional ◽

Icu Admission ◽

Race Ethnicity ◽

Introduction: Individual pre-pregnancy risk factors such as obesity, hypertension, and diabetes disproportionately affect minority women and are associated with adverse maternal and offspring outcomes. However, quantification of pre-pregnancy cardiovascular health (CVH) and association with pregnancy outcomes is lacking and can help identify at-risk women and children. Hypothesis: Suboptimal pre-pregnancy CVH is associated with higher risk of adverse maternal and fetal outcomes. Methods: We conducted a cross-sectional study using the CDC Natality files, which include all pregnancies in the US that resulted in live birth or fetal death after 20 weeks. Our study sample consisted of data from singleton live births or fetal deaths to women aged 15-44 years in 2018. Four maternal metrics (body mass index, smoking, diabetes, and hypertension) were assigned 1 point each for pre-pregnancy BMI < 25.0 kg/m 2 , non-smoking, and absence of hypertension or diabetes to construct a pre-pregnancy clinical CVH score ranging from 0-4. We examined the distribution of CVH by race/ethnicity. We then quantified associations of CVH with maternal ICU admission, preterm birth (PTB), low birthweight (LBW), and fetal death using logistic regression (CVH = 4 as the referent) adjusted for maternal age, race/ethnicity, education, prenatal care, and parity. Results: Of 3,582,832 pregnancies in 2018, more than half of women had a suboptimal CVH score (CVH = 3: 51.8%; CVH = 2: 6.7%; CVH = 0/1: 0.4%). Suboptimal CVH score (<4) was more prevalent in non-Hispanic Black (67.8%) and Hispanic (63.1%) than in non-Hispanic White (57.2%) and Asian (36.8%) women ( Figure) . There were consistent and inverse graded associations between CVH score of 3, 2, and 0/1 (compared with 4 as the referent) and maternal ICU admission, PTB, LBW, and fetal death (p<0.001). Conclusions: Pre-pregnancy clinical CVH score has strong, graded associations with adverse maternal and fetal outcomes, with disproportionate impact of suboptimal CVH in non-Hispanic Black and Hispanic women.

Hypertension in Metabolic Syndrome: Novel Insights

Current Hypertension Reviews ◽

10.2174/1573402115666190415161813 ◽

2020 ◽

Vol 16 (1) ◽

pp. 12-18 ◽

Cited By ~ 1

Author(s):

Alexandra Katsimardou ◽

Konstantinos Imprialos ◽

Konstantinos Stavropoulos ◽

Alexandros Sachinidis ◽

Michalis Doumas ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adult Population ◽

Channel Blockers ◽

Cvd Risk ◽

The Metabolic Syndrome ◽

Drug Classes ◽

High Prevalence ◽

Metabolic Properties ◽

Background: Metabolic syndrome (MetS) is characterized by the simultaneous presence of obesity, hypertension, dyslipidemia and hyperglycemia in an individual, leading to increased cardiovascular disease (CVD) risk. It affects almost 35% of the US adult population, while its prevalence increases with age. Elevated blood pressure is the most frequent component of the syndrome; however, until now, the optimal antihypertensive regiment has not been defined. Objective: The purpose of this review is to present the proposed definitions for the metabolic syndrome, as well as the prevalence of hypertension in this condition. Moreover, evidence regarding the metabolic properties of the different antihypertensive drug classes and their effect on MetS will be displayed. Method: A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, pathophysiology and treatment of hypertension in the metabolic syndrome. Results: Hypertension is present in almost 80% of patients with metabolic syndrome. The use of thiazide diuretics and b-blockers has been discouraged in this population; however, new evidence suggests their use under specific conditions. Calcium channel blockers seem to exert a neutral effect on MetS, while renin-angiotensin system inhibitors are believed to be of the most benefit, although differences exist between the different agents of this category. Conclusion: Controversy still exists regarding the optimal antihypertensive treatment for hypertension in MetS. Due to the high prevalence of hypertension in this population, more data from clinical trials are needed in the future.

A novel landscape of nuclear human CDK2 substrates revealed by in situ phosphorylation

Science Advances ◽

10.1126/sciadv.aaz9899 ◽

2020 ◽

Vol 6 (16) ◽

pp. eaaz9899

Author(s):

Yong Chi ◽

John H. Carter ◽

Jherek Swanger ◽

Alexander V. Mazin ◽

Robert L. Moritz ◽

...

Keyword(s):

Cell Division ◽

Protein Complexes ◽

Nuclear Architecture ◽

Cyclin Dependent Kinase ◽

Oncogenic Signaling ◽

Cellular Processes ◽

Validation Rate ◽

Associated Proteins ◽

Epigenetic Regulators

Cyclin-dependent kinase 2 (CDK2) controls cell division and is central to oncogenic signaling. We used an “in situ” approach to identify CDK2 substrates within nuclei isolated from cells expressing CDK2 engineered to use adenosine 5′-triphosphate analogs. We identified 117 candidate substrates, ~40% of which are known CDK substrates. Previously unknown candidates were validated to be CDK2 substrates, including LSD1, DOT1L, and Rad54. The identification of many chromatin-associated proteins may have been facilitated by labeling conditions that preserved nuclear architecture and physiologic CDK2 regulation by endogenous cyclins. Candidate substrates include proteins that regulate histone modifications, chromatin, transcription, and RNA/DNA metabolism. Many of these proteins also coexist in multi-protein complexes, including epigenetic regulators, that may provide new links between cell division and other cellular processes mediated by CDK2. In situ phosphorylation thus revealed candidate substrates with a high validation rate and should be readily applicable to other nuclear kinases.