heparitin-sulfate and Hypertension

Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 19 disease (COVID-19) which presents a large spectrum of manifestations with fatal outcomes in vulnerable people over 70-years-old and with hypertension, diabetes, obesity, cardiovascular disease, COPD, and smoking status. Knowledge of the entry receptor is key to understand SARS-CoV-2 tropism, transmission and pathogenesis. Early evidence pointed to angiotensin-converting enzyme 2 (ACE2) as SARS-CoV-2 entry receptor. Here, we provide a critical summary of the current knowledge highlighting the limitations and remaining gaps that need to be addressed to fully characterize ACE2 function in SARS-CoV-2 infection and associated pathogenesis. We also discuss ACE2 expression and potential role in the context of comorbidities associated with poor COVID-19 outcomes. Finally, we discuss the potential co-receptors/attachment factors such as neuropilins, heparan sulfate and sialic acids and the putative alternative receptors, such as CD147 and GRP78.

Topics: Angiotensin-Converting Enzyme 2; Basigin; Betacoronavirus; Comorbidity; Coronavirus Infections; COVID-19; Endoplasmic Reticulum Chaperone BiP; Gene Expression Regulation, Enzymologic; Heparitin Sulfate; Humans; Hypertension; Neuropilin-1; Oligopeptides; Organ Specificity; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Receptors, Virus; Renin-Angiotensin System; Respiratory System; RNA, Messenger; SARS-CoV-2; Sialic Acids; Spike Glycoprotein, Coronavirus; Virus Attachment; Virus Internalization

Pre-eclampsia (PE) remains the leading cause of pregnancy-associated mortality and morbidity, urging the need for a better understanding of its aetiology and pathophysiological progression. A key characteristic of PE is a systemic, exaggerated, inflammatory condition involving abnormal cytokine levels in serum, altered immune cell phenotype and Th1/Th2-type immunological imbalance. However, it is unknown how this heightened inflammatory condition manifests. We previously reported increased expression of the lipopolysaccharide receptor, Toll-like receptor 4 (TLR4), on monocytes from PE patients compared with normotensive, pregnant patients (NP). This upregulation of TLR4 on PE monocytes was accompanied by a hyper-responsiveness to bacterial TLR4 ligands. To determine whether non-microbial, endogenous TLR4 ligands also activate monocytes from PE patients, we investigated the expression of host-derived TLR4 ligands and the response of monocytes to these endogenous ligands. Plasma levels of fibrinogen - but not fibronectin or heparan sulphate - were higher in PE patients than in NP. Exposure to fibrinogen was associated with significantly increased production of inflammatory cytokines by monocytes from PE patients. Interestingly, this effect was not observed with NP monocytes. Our findings suggest that the fibrinogen-TLR4 axis might play an important role in the atypical activation of monocytes observed in PE patients that may contribute to the exaggerated inflammatory condition.

Topics: Adult; Cytokines; Female; Fibrinogen; Fibronectins; Heparitin Sulfate; Humans; Hypertension; Inflammation; Monocytes; Pre-Eclampsia; Pregnancy; Proteinuria; Toll-Like Receptor 4

Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; 4, 8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L-NAME (N(ω)-nitro-L-arginine-methylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-α and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg(-1) per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg(-1) per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg(-1) per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiomegaly; Chemokine CCL2; Heparitin Sulfate; Hypertension; Interleukin-6; Myocardium; NG-Nitroarginine Methyl Ester; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Up-Regulation

Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

Topics: Animals; Anticoagulants; Cell Line; Heparin; Heparitin Sulfate; Humans; Hypertension; Interferon-gamma; Intestinal Mucosa; Mice; Mice, Knockout; Protein-Losing Enteropathies; Syndecan-1; Tumor Necrosis Factor-alpha

Pathogenesis, frequency, and management of heparin-induced thrombocytopaenia are well-known. They may be related with both unfractioned heparin and low-molecular weight heparin. Suspected heparin must be discontinued as soon as the diagnosis is established. Orgaran (danaparoid sodium) may be used for management of patients with heparin-associated thrombocytopaenia but can itself be associated with a thrombocytopaenia. Our case report allows us to catch in mind such a crossed complication.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Captopril; Carotid Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Hypertension; Stroke; Thrombocytopenia

Heparan sulfate proteoglycans are major components of the glomerular basement membrane and play a key role in the molecular organization and function of the basement membrane. Moreover, their presence is essential for maintenance of the selective permeability of the glomerular basement membrane. Recently, we isolated and characterized a novel small basement membrane-associated heparan sulfate proteoglycan from human aorta and kidney. Partial amino acid sequence data clearly show that this heparan sulfate proteoglycan is distinct from the large basement membrane-associated heparan sulfate proteoglycan (perlecan). Using specific monoclonal antibodies, we have shown that the novel heparan sulfate proteoglycan is located predominantly in the glomerular basement membrane and, to a lesser extent, in the basement membrane of tubuli. Turnover or, in the course of kidney diseases, degradation of heparan sulfate proteoglycan from glomerular basement membranes may lead to urinary excretion of heparan sulfate proteoglycan, which can be measured by a sensitive enzyme immunoassay. The aim of the present study was to analyze whether changes in the structure and function of glomerular basement membranes can be directly detected by measurement of the excretion of a component of this basement membrane, eg, heparan sulfate proteoglycan into urine. The excretion of this small heparan sulfate proteoglycan was compared after physical exercise in normotensive and hypertensive subjects. Normotensive subjects and treated, essential hypertensive patients underwent a standardized workload on a bicycle ergometer. Biochemical characterization of the urinary proteins and heparan sulfate proteoglycan was performed before and 15 and 45 minutes after exercises.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Basement Membrane; Female; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Hypertension; Immunohistochemistry; Kidney Glomerulus; Male; Middle Aged; Mucoproteins; Physical Exertion; Proteinuria; Proteoglycans; Reference Values; Uromodulin

The effect of short term (8 weeks) sodium (Na+) depletion and its repletion on glomerular synthesis of heparan sulfate and urinary excretions of albumin, total protein, heparan sulfate, Na+ and potassium (K+) was studied in spontaneous hypertensive rats (SHR) and their control normotensive Wistar-Kyoto rats (WKY). Na+ depletion in SHRs significantly increased the synthesis of glomerular heparan sulfate and decreased urinary excretions of albumin, Na+ and heparan sulfate when compared with the Na+ repleted group. In WKY rats, Na+ depletion did not cause any of the above changes. These data suggest that Na+ depletion prevents the urinary loss of protein through preservation of glomerular heparan sulfate only in SHRs.

Topics: Albuminuria; Animals; Blood Pressure; Body Weight; Drinking; Glycosaminoglycans; Heparitin Sulfate; Hypertension; Kidney Glomerulus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium

A coarctation hypertensive rat model was used to examine the effects of elevated blood pressure on basement membrane component synthesis by cardiac myocytes and aorta using immunohistochemistry and Northern blot analysis. Carotid arterial pressure increased immediately on coarctation, and left ventricular hypertrophy was maximal within 5 days. In immunohistochemical studies, fibronectin and laminin were increased and the basement membrane chondroitin sulfate proteoglycan decreased in both the subendothelial space and smooth muscle cell basement membranes of the aorta above the clip compared with controls, whereas only fibronectin was elevated in the aorta below the clip. No change in basement membrane staining intensity for the cardiac myocytes was observed. Alterations in steady-state mRNA levels for fibronectin and laminin in the aorta paralleled those observed by immunohistochemical analysis with regard to protein and tissue type affected as well as intensity of the changes. However, changes in mRNA levels (but not protein deposition) for perlecan and type IV collagen were also observed in aortas from hypertensive rats compared with controls. Increases in steady-state mRNA levels for all basement membrane components in the heart and vasculature peaked before maximal cardiac hypertrophy (5 days). These studies indicate that alterations in basement membrane component deposition in the hypertrophied vasculature occur at both transcriptional and translational levels and suggest that the cell attachment glycoproteins fibronectin and laminin may be important factors in the vascular response to elevated transmural pressure.

Topics: Animals; Aorta, Abdominal; Aortic Coarctation; Basement Membrane; Blood Pressure; Body Weight; Carotid Arteries; Collagen; DNA Probes; Fibronectins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Hypertension; Laminin; Male; Muscle, Smooth, Vascular; Organ Size; Proteoglycans; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors

Topics: Animals; Basement Membrane; Blood Pressure; Capillary Permeability; Glomerular Filtration Rate; Heparitin Sulfate; Humans; Hypertension; Kidney Glomerulus; Rats; Rats, Inbred Strains; Water