Nanobody-thioesterase chimeras to specifically target protein palmitoylation.

The complexity of the cellular proteome is massively expanded by a repertoire of chemically distinct reversible post-translational modifications (PTMs) that control protein localisation, interactions, and function. The temporal and spatial control of these PTMs is central to organism physiology, and mis-regulation of PTMs is a hallmark of many diseases. Here we present an approach to manipulate PTMs on target proteins using nanobodies fused to enzymes that control these PTMs.

SUMOylation of cardiac myosin binding protein-C reduces its phosphorylation and results in impaired relaxation following treatment with isoprenaline.

Systolic and diastolic functions are coordinated in the heart by myofilament proteins that influence force of contraction and calcium sensitivity. Fine control of these processes is afforded by a variety of post-translation modifications that occur on specific proteins at different times during each heartbeat. Cardiac myosin binding protein-C is a sarcomeric accessory protein whose function is to interact transiently with actin, tropomyosin and myosin.

Insights into Uromodulin and Blood Pressure.

Purpose Of Review: We review the role of uromodulin, a protein exclusively expressed in the kidney, in blood pressure regulation and hypertension.

Recent Findings: The last few years have seen a shift of focus from genetic association to mendelian randomisation and uromodulin-salt interaction studies, thus confirming the causal role of uromodulin in blood pressure regulation and hypertension. This work has been complemented by phenome-wide association studies in a wider range of ethnicities.

Pregnancy-associated changes in urinary uromodulin excretion in chronic hypertension.

Background: Pregnancy involves major adaptations in renal haemodynamics, tubular, and endocrine functions. Hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity. Uromodulin is a nephron-derived protein that is associated with hypertension and kidney diseases.

Urinary Peptidomics and Pulse Wave Velocity: The African-PREDICT Study.

Increased arterial stiffness is related to early vascular aging and is an independent predictor for cardiovascular disease and mortality. Molecular mechanisms underlying increased arterial stiffness are largely unexplored, especially at the proteome level. We aimed to explore the relationship between pulse wave velocity and urinary proteomics.

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication.

COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important. Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process.

Identifying a urinary peptidomics profile for hypertension in young adults: The African-PREDICT study: Urinary peptidomics and hypertension: Urinary peptidomics and hypertension.

Hypertension is one of the most important and complex risk factors for cardiovascular diseases (CVDs). By using urinary peptidomics analyses, we aimed to identify peptides associated with hypertension, building a framework for future research towards improved prediction and prevention of premature development of CVD. We included 78 hypertensive and 79 normotensive participants from the African-PREDICT study (aged 20-30 years), matched for sex (51% male) and ethnicity (49% black and 51% white).

Skin-specific mechanisms of body fluid regulation in hypertension.

Increasing evidence suggests excess skin Na+ accumulation in hypertension; however, the role of skin-specific mechanisms of local Na+/water regulation remains unclear. We investigated the association between measures of sweat and trans-epidermal water loss (TEWL) with Na+ content in the skin ([Na+]skin) and clinical characteristics in consecutive hypertensive patients. We obtained an iontophoretic pilocarpine-induced sweat sample, a skin punch biopsy for chemical analysis, and measures of TEWL from the upper limbs.

A urinary peptidomics approach for early stages of cardiovascular disease risk: The African-PREDICT study.

Cardiovascular disease (CVD) affects individuals across the lifespan, with multiple cardiovascular (CV) risk factors increasingly present in young populations. The underlying mechanisms in early cardiovascular disease development are complex and still poorly understood. We therefore employed urinary proteomics as a novel approach to gain better insight into early CVD-related molecular pathways based on a CVD risk stratification approach.

Role of Uromodulin in Salt-Sensitive Hypertension.

The exclusive expression of uromodulin in the kidneys has made it an intriguing protein in kidney and cardiovascular research. Genome-wide association studies discovered variants of uromodulin that are associated with chronic kidney diseases and hypertension. Urinary and circulating uromodulin levels reflect kidney and cardiovascular health as well as overall mortality.

Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7.

The bifunctional cation channel/kinase TrpM7 is ubiquitously expressed and regulates embryonic development and pathogenesis of several common diseases. The TrpM7 integral membrane ion channel domain regulates transmembrane movement of divalent cations, and its kinase domain controls gene expression via histone phosphorylation. Mechanisms regulating TrpM7 are elusive.

Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats.

Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending limb (TAL) epithelial cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. We aimed to dissect the role of dietary salt in renal UMOD excretion in normotension and chronic hypertension.

Mechanistic interactions of uromodulin with the thick ascending limb: perspectives in physiology and hypertension.

Hypertension is a significant risk factor for cardiovascular disease and mortality worldwide. The kidney is a major regulator of blood pressure and electrolyte homeostasis, with monogenic disorders indicating a link between abnormal ion transport and salt-sensitive hypertension. However, the association between salt and hypertension remains controversial.

Preexisting hypertension and pregnancy-induced hypertension reveal molecular differences in placental proteome in rodents.

Preexisting or new onset of hypertension affects pregnancy and is one of the leading causes of maternal and fetal morbidity and mortality. In certain cases, it also leads to long-term maternal cardiovascular complications. The placenta is a key player in the pathogenesis of complicated hypertensive pregnancies, however the pathomechanisms leading to an abnormal placenta are poorly understood.

Reduced Lymphatic Reserve in Heart Failure With Preserved Ejection Fraction.

Background: Microvascular dysfunction plays an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link between systemic microvasculature and congestion, a central feature of the syndrome, has yet been investigated.

Objectives: This study aimed to investigate capillary-interstitium fluid exchange in HFpEF, including lymphatic drainage and the potential osmotic forces exerted by any hypertonic tissue Na excess.

High sodium intake, glomerular hyperfiltration, and protein catabolism in patients with essential hypertension.

Aims: A blood pressure (BP)-independent metabolic shift towards a catabolic state upon high sodium (Na+) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. We sought to investigate the real-life impact of high Na+ intake on measures of renal Na+/water handling and metabolic signatures, as surrogates for cardiovascular risk, in hypertensive patients.

Methods And Results: We analysed clinical and biochemical data from 766 consecutive patients with essential hypertension, collected at the time of screening for secondary causes.

Tissue sodium excess is not hypertonic and reflects extracellular volume expansion.

Our understanding of Na homeostasis has recently been reshaped by the notion of skin as a depot for Na accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na excess upon high Na intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.

Resistin Mediates Sex-Dependent Effects of Perivascular Adipose Tissue on Vascular Function in the Shrsp.

Premenopausal women are relatively protected from developing hypertension compared to men. Perivascular adipose tissue (PVAT) has been shown to mediate vasoactive effects; however, a sex-dependent difference in PVAT function in the setting of hypertension has not yet been explored. We investigated the effect of PVAT on resistance vessel biology in male and female 16 week old stroke prone spontaneously hypertensive rats (SHRSP).

Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria.

Background: The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown.

Methods: Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria.

Polymerization-Incompetent Uromodulin in the Pregnant Stroke-Prone Spontaneously Hypertensive Rat.

The kidney is centrally involved in blood pressure regulation and undergoes extensive changes during pregnancy. Hypertension during pregnancy may result in an altered urinary peptidome that could be used to indicate new targets of therapeutic or diagnostic interest. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of maternal chronic hypertension.

Tubulointerstitial nephritis antigen-like 1 protein is downregulated in the placenta of pre-eclamptic women.

Background: Tubulointerstitial nephritis antigen-like 1 protein (TINAGL1), is a matricellular protein, known to play role in cell adhesion and cell receptor interaction. Research related to TINAGL1 is limited to cell culture and animal models. Demonstration of TINAGL1 as a positive regulator of angiogenesis and its expression in the decidua of postimplantation mouse uterus, prompted us to validate its expression in human placenta during impaired angiogenesis in pre-eclamptic condition.

Placental Proteomics Provides Insights into Pathophysiology of Pre-Eclampsia and Predicts Possible Markers in Plasma.

Pre-eclampsia is a hypertensive disorder characterized by the new onset of hypertension >140/90 mmHg and proteinuria after the 20th week of gestation. The disorder is multifactorial and originates with abnormal placentation. Comparison of the placental proteome of normotensive (n = 25) and pre-eclamptic (n = 25) patients by gel-free proteomic techniques identified a total of 2145 proteins in the placenta of which 180 were differentially expressed (>1.

Immune response to chemically modified proteome.

Both enzymatic and nonenzymatic PTMs of proteins involve chemical modifications. Some of these modifications are prerequisite for the normal functioning of cell, while other chemical modifications render the proteins as "neo-self" antigens, which are recognized as "non-self" leading to aberrant cellular and humoral immune responses. However, these modifications could be a secondary effect of autoimmune diseases, as in the case of type I diabetes, hyperglycemia leads to protein glycation.