ABSTRACT
BACKGROUND: Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking. OBJECTIVES: We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice. DESIGN, PATIENTS, AND MEASUREMENTS: The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism. RESULTS: The incidence of low-FT4 varied according to FT4 assay method (range: 98-301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%-4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates. CONCLUSIONS: Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities.
Subject(s)
Hypothyroidism , Thyroid Function Tests , Thyrotropin , Thyroxine , Humans , Hypothyroidism/diagnosis , Hypothyroidism/blood , Hypothyroidism/epidemiology , Thyrotropin/blood , Middle Aged , Female , Adult , Male , Thyroxine/blood , Aged , Young Adult , Adolescent , Mass Screening/methods , IncidenceABSTRACT
AIMS: Endothelial dysfunction and arterial stiffness are hallmarks of hypertension, and major risk factors for cardiovascular disease. BPH/2J (Schlager) mice are a genetic model of spontaneous hypertension, but little is known about the vascular pathophysiology of these mice and the region-specific differences between vascular beds. Therefore, this study compared the vascular function and structure of large conductance (aorta and femoral) and resistance (mesenteric) arteries of BPH/2J mice with their normotensive BPN/2J counterparts. MAIN METHODS: Blood pressure was measured in BPH/2J and BPN/3J mice via pre-implanted radiotelemetry probes. At endpoint, vascular function and passive mechanical wall properties were assessed using wire and pressure myography, qPCR and histology. KEY FINDINGS: Mean arterial blood pressure was elevated in BPH/2J mice compared to BPN/3J controls. Endothelium-dependent relaxation to acetylcholine was attenuated in both the aorta and mesenteric arteries of BPH/2J mice, but through different mechanisms. In the aorta, hypertension reduced the contribution of prostanoids. Conversely, in the mesenteric arteries, hypertension reduced the contribution of both nitric oxide and endothelium-dependent hyperpolarization. Hypertension reduced volume compliance in both femoral and mesenteric arteries, but hypertrophic inward remodelling was only observed in the mesenteric arteries of BPH/2J mice. SIGNIFICANCE: This is the first comprehensive investigation of vascular function and structural remodelling in BPH/2J mice. Overall, hypertensive BPH/2J mice exhibited endothelial dysfunction and adverse vascular remodelling in the macro- and microvasculature, underpinned by distinct region-specific mechanisms. This highlights BPH/2J mice as a highly suitable model for evaluating novel therapeutics to treat hypertension-associated vascular dysfunction.
Subject(s)
Hypertension , Animals , Mice , Arteries/pathology , Blood Pressure/physiology , Endothelium/pathology , Endothelium, Vascular/pathology , Mesenteric Arteries , Sympathetic Nervous System/physiology , VasodilationABSTRACT
BACKGROUND: The peptide hormone relaxin has potent anti-fibrotic and anti-inflammatory properties in various organs, including the kidneys. However, the protective effects of relaxin in the context of diabetic kidney complications remain controversial. Here, we aimed to evaluate the effects of relaxin treatment on key markers of kidney fibrosis, oxidative stress, and inflammation and their subsequent impact on bile acid metabolism in the streptozotocin-induced diabetes mouse model. METHODS AND RESULTS: Male mice were randomly allocated to placebo-treated control, placebo-treated diabetes or relaxin-treated diabetes groups (0.5 mg/kg/d, final 2 weeks of diabetes). After 12 weeks of diabetes or sham, the kidney cortex was harvested for metabolomic and gene expression analyses. Diabetic mice exhibited significant hyperglycaemia and increased circulating levels of creatine, hypoxanthine and trimethylamine N-oxide in the plasma. This was accompanied by increased expression of key markers of oxidative stress (Txnip), inflammation (Ccl2 and Il6) and fibrosis (Col1a1, Mmp2 and Fn1) in the diabetic kidney cortex. Relaxin treatment for the final 2 weeks of diabetes significantly reduced these key markers of renal fibrosis, inflammation, and oxidative stress in diabetic mice. Furthermore, relaxin treatment significantly increased the levels of bile acid metabolites, deoxycholic acid and sodium glycodeoxycholic acid, which may in part contribute to the renoprotective action of relaxin in diabetes. CONCLUSION: In summary, this study shows the therapeutic potential of relaxin and that it may be used as an adjunctive treatment for diabetic kidney complications.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Relaxin , Animals , Mice , Male , Diabetic Nephropathies/drug therapy , Diabetes Mellitus, Experimental/drug therapy , Relaxin/pharmacology , Streptozocin/pharmacology , Kidney , Oxidative Stress , Inflammation/drug therapy , FibrosisABSTRACT
In brief: There is a pregnancy-induced vasodilation of blood vessels, which is known to have a protective effect on cardiovascular function and can be maintained postpartum. This review outlines the cardiovascular changes that occur in a healthy human and rodent pregnancy, as well as different pathways that are activated by angiotensin II and relaxin that result in blood vessel dilation. Abstract: During pregnancy, systemic and uteroplacental blood flow increase to ensure an adequate blood supply that carries oxygen and nutrients from the mother to the fetus. This results in changes to the function of the maternal cardiovascular system. There is also a pregnancy-induced vasodilation of blood vessels, which is known to have a protective effect on cardiovascular health/function. Additionally, there is evidence that the effects of maternal vascular vasodilation are maintained post-partum, which may reduce the risk of developing high blood pressure in the next pregnancy and reduce cardiovascular risk later in life. At both non-pregnant and pregnant stages, vascular endothelial cells produce a number of vasodilators and vasoconstrictors, which transduce signals to the contractile vascular smooth muscle cells to control the dilation and constriction of blood vessels. These vascular cells are also targets of other vasoactive factors, including angiotensin II (Ang II) and relaxin. The binding of Ang II to its receptors activates different pathways to regulate the blood vessel vasoconstriction/vasodilation, and relaxin can interact with some of these pathways to induce vasodilation. Based on the available literature, this review outlines the cardiovascular changes that occur in a healthy human pregnancy, supplemented by studies in rodents. A specific focus is placed on vasodilation of blood vessels during pregnancy; the role of endothelial cells and endothelium-derived vasodilators will also be discussed. Additionally, different pathways that are activated by Ang II and relaxin that result in blood vessel dilation will also be reviewed.
Subject(s)
Angiotensin II , Relaxin , Endothelial Cells/metabolism , Endothelium, Vascular , Female , Humans , Oxygen/metabolism , Oxygen/pharmacology , Pregnancy , Relaxin/metabolism , Vasoconstrictor Agents/metabolism , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: The evidence to guide the management of asymptomatic radiologically-detected anastomotic leakages (ARAL) following anterior resection (AR) with diverting ileostomy is deficient. This study describes the outcomes of managing ARAL one of the UK teaching hospitals. METHOD: The study included all patients diagnosed with ARAL following AR during 8 years period (2012-2020). The following data were retrospectively collected: patient demographics, surgical indication, anastomotic technique, tumour staging, neoadjuvant therapy, how ARAL was managed, the outcomes and duration to heal and ileostomy reversal. RESULTS: A total of 35 patients (M = 24) who developed ARAL during the study period were included. In 32 patients, AR was performed for rectal cancer. All patients with ARAL were treated conservatively and in 31 (89%) patients, there was complete resolution of the leakage within a median duration of 6 months. Covering loop ileostomies were reversed in 26 (74%) patients with a median interval to reversal of 10 months. CONCLUSION: Most asymptomatic radiologically-detected anastomotic leakages after anterior resection heal with conservative treatment in the presence of a covering loop ileostomy with an expected average delay of 6 months for the leakage to heal before covering ileostomies can be reversed.
Subject(s)
Anastomotic Leak , Rectal Neoplasms , Anastomosis, Surgical/adverse effects , Anastomotic Leak/diagnostic imaging , Anastomotic Leak/etiology , Humans , Ileostomy/adverse effects , Ileostomy/methods , Rectal Neoplasms/surgery , Retrospective StudiesABSTRACT
AIMS: The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, ß-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery. METHODS AND RESULTS: In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation), and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy. In contrast, rAAV6-OGA (but not rAAV6-OGT) rescued LV diastolic function and adverse cardiac remodelling in diabetic mice. Molecular insights implicated impaired cardiac PI3K(p110α)-Akt signalling as a potential contributing mechanism to the detrimental consequences of rAAV6-OGT in vivo. In contrast, rAAV6-OGA preserved PI3K(p110α)-Akt signalling in diabetic mouse myocardium in vivo and prevented high glucose-induced impairments in mitochondrial respiration in human cardiomyocytes in vitro. CONCLUSION: Maladaptive protein O-GlcNAc modification is evident in human diabetic myocardium, and is a critical regulator of the diabetic heart phenotype. Selective targeting of cardiac protein O-GlcNAcylation to restore physiological O-GlcNAc balance may represent a novel therapeutic approach for diabetes-induced heart failure.
Subject(s)
Antigens, Neoplasm/metabolism , Diabetic Cardiomyopathies/enzymology , Histone Acetyltransferases/metabolism , Hyaluronoglucosaminidase/metabolism , Myocytes, Cardiac/enzymology , N-Acetylglucosaminyltransferases/metabolism , Protein Processing, Post-Translational , Ventricular Dysfunction, Left/enzymology , Ventricular Function, Left , Ventricular Remodeling , Aged , Animals , Antigens, Neoplasm/genetics , Cell Line , Class I Phosphatidylinositol 3-Kinases/metabolism , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/physiopathology , Disease Models, Animal , Female , Fibrosis , Gene Expression Regulation , Glycosylation , Histone Acetyltransferases/genetics , Humans , Hyaluronoglucosaminidase/genetics , Male , Mice , Middle Aged , Myocytes, Cardiac/pathology , N-Acetylglucosaminyltransferases/genetics , Phenotype , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , Ventricular Dysfunction, Left/genetics , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathologyABSTRACT
We report a case of a generally fit and well 54-year-old man who presented with a 2-day history of worsening left-sided otorrhea, headache, neck stiffness, vomiting and fever on the background of a 7-week history of otitis externa (OE). His condition progressed dramatically as he developed symptoms consistent with acute complete cervical cord syndrome with radiological evidence of skull base osteomyelitis, parapharyngeal, retropharyngeal and paravertebral abscesses and sigmoid sinus thrombus. Ultimately, he made a significant, although not complete, recovery. This case is unique in demonstrating how OE can develop into a potentially life threatening condition. It emphasises the importance of early diagnosis and treatment of OE, the recognition of 'red flag' symptoms and highlights the importance of a multidisciplinary team approach when managing complex complications of OE.
Subject(s)
Cervical Cord , Osteomyelitis , Otitis Externa , Cervical Cord/diagnostic imaging , Humans , Male , Middle Aged , Otitis Externa/complications , Otitis Externa/diagnosis , Paralysis , Skull BaseABSTRACT
Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly, the more prevalent type 2 diabetes patient population. In the current study, we investigated whether administration of recombinant adeno-associated viral vectors carrying a constitutively active phosphoinositide 3-kinase (PI3K)(p110α) construct (rAAV6-caPI3K) at a clinically relevant time point attenuates diabetic cardiomyopathy in a preclinical type 2 diabetes (T2D) model. T2D was induced by a combination of a high-fat diet (42% energy intake from lipid) and low-dose streptozotocin (three consecutive intraperitoneal injections of 55 mg/kg body wt), and confirmed by increased body weight, mild hyperglycemia, and impaired glucose tolerance (all P < 0.05 vs. nondiabetic mice). After 18 wk of untreated diabetes, impaired left ventricular (LV) systolic dysfunction was evident, as confirmed by reduced fractional shortening and velocity of circumferential fiber shortening (Vcfc, all P < 0.01 vs. baseline measurement). A single tail vein injection of rAAV6-caPI3K gene therapy (2×1011vector genomes) was then administered. Mice were followed for an additional 8 wk before end point. A single injection of cardiac targeted rAAV6-caPI3K attenuated diabetes-induced cardiac remodeling by limiting cardiac fibrosis (reduced interstitial and perivascular collagen deposition, P < 0.01 vs. T2D mice) and cardiomyocyte hypertrophy (reduced cardiomyocyte size and Nppa gene expression, P < 0.001 and P < 0.05 vs. T2D mice, respectively). The diabetes-induced LV systolic dysfunction was reversed with rAAV6-caPI3K, as demonstrated by improved fractional shortening and velocity of circumferential fiber shortening (all P < 0.05 vs pre-AAV measurement). This cardioprotection occurred in combination with reduced LV reactive oxygen species (P < 0.05 vs. T2D mice) and an associated decrease in markers of endoplasmic reticulum stress (reduced Grp94 and Chop, all P < 0.05 vs. T2D mice). Together, our findings demonstrate that a cardiac-selective increase in PI3K(p110α), via rAAV6-caPI3K, attenuates T2D-induced diabetic cardiomyopathy, providing proof of concept for potential translation to the clinic.NEW & NOTEWORTHY Diabetes remains a major cause of death and disability worldwide (and its resultant heart failure burden), despite current care. The lack of existing management of heart failure in the context of the poorer prognosis of concomitant diabetes represents an unmet clinical need. In the present study, we now demonstrate that delayed intervention with PI3K gene therapy (rAAV6-caPI3K), administered as a single dose in mice with preexisting type 2 diabetes, attenuates several characteristics of diabetic cardiomyopathy, including diabetes-induced impairments in cardiac remodeling, oxidative stress, and function. Our discovery here contributes to the previous body of work, suggesting the cardioprotective effects of PI3K(p110α) could be a novel therapeutic approach to reduce the progression to heart failure and death in diabetes-affected patients.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Diabetes Mellitus, Type 2/complications , Diabetic Cardiomyopathies/therapy , Genetic Therapy/methods , Animals , Class I Phosphatidylinositol 3-Kinases/metabolism , Dependovirus/genetics , Dependovirus/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/etiology , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/pathology , Diet, High-Fat/adverse effects , Endoplasmic Reticulum Stress , Fibrosis , Genetic Vectors/genetics , Genetic Vectors/metabolism , Male , Mice , Myocardium/metabolism , Reactive Oxygen Species , Ventricular RemodelingABSTRACT
Purpose: To test if relaxin deficiency affects ocular structure and function we investigated expression of relaxin (Rln) and RXFP receptors (Rxfp1, Rxfp2), and compared ocular phenotypes in relaxin gene knockout (Rln-/- ) and wild type (Rln+/+ ) mice. Materials and Methods: Rln, Rxfp1 and Rxfp2 mRNA expression was detected in ocular tissues of Rln+/+ mice using RT-PCR. The eyes of 11 Rln-/- and 5 Rln+/+ male mice were investigated. Corneal and retinal thickness was assessed using optical coherence tomography. Intraocular pressure was measured using a rebound tonometer. Retinal, choroidal and sclera morphology and thickness were evaluated histologically. Eyes were collected and fixed for immunofluorescence staining or used for RNA extraction to evaluate mRNA expression using real-time PCR. Results: Rln mRNA was expressed only in the retina, whereas Rxfp1 transcripts were detected in the retina, cornea and sclera/choroid. Rxfp2 was only present in the cornea. None of these genes were expressed in the lacrimal gland, eyelid or lens. Intraocular pressure was higher and central cornea of Rln-/- mice was significantly thicker and had significantly larger endothelial cells and a lower endothelial cell density than Rln+/+ mice. Immunohistochemistry demonstrated no significant difference in AQP3 and AQP5 staining in the cornea or other regions between wildtype and Rln-/- mice. mRNA expression of Aqp4 was significantly higher in Rln-/- than in Rln+/+ corneas, whereas Col1a2, Mmp9, Timp1 and Timp2 were significantly decreased. Expression of Aqp1, Aqp4, Aqp5, Vim and Tjp1 was significantly decreased in Rln-/- compared to Rln+/+ uvea. No significant differences in these genes were detected in the retina. Retinal, choroidal and scleral thicknesses were not different and morphology appeared normal. Conclusion: The findings indicate that loss of Rln affects expression of several genes in the uvea and cornea and results in thicker corneas with altered endothelial cells. Many of the gene changes suggest alterations in extracellular matrix and fluid transport between cells.
Subject(s)
Aquaporins/genetics , Cornea/metabolism , Extracellular Matrix Proteins/genetics , Gene Expression Regulation/physiology , Relaxin/genetics , Animals , Choroid/metabolism , Choroid/pathology , Cornea/pathology , Female , Gene Knockout Techniques , Intraocular Pressure/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, G-Protein-Coupled/genetics , Retina/metabolism , Retina/pathology , Sclera/metabolism , Sclera/pathology , Tomography, Optical Coherence , Tonometry, OcularABSTRACT
The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.
Subject(s)
Annexin A1/metabolism , Diabetes Mellitus, Experimental/drug therapy , Protective Agents/therapeutic use , Small Molecule Libraries/therapeutic use , Animals , Aorta/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/blood , Male , Mice, Inbred C57BL , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Protective Agents/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Formyl Peptide/metabolism , Small Molecule Libraries/pharmacology , Streptozocin , Vasodilator Agents/pharmacologyABSTRACT
Aim: Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NOâ¢), known as NO⢠resistance, occurs in many cardiovascular disease states, prominently in diabetes and especially in the presence of marked hyperglycemia. In this study, we sought to determine in moderate and severe diabetes (i) whether NO⢠resistance also occurs in the myocardium, and (ii) whether the NO⢠redox sibling nitroxyl (HNO) circumvents this. Results: The spectrum of acute NO⢠effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabetic rats ([blood glucose] â¼20 mM). In contrast, acute HNO effects (induced by isopropylamine-NONOate) were preserved even in more severe diabetes ([blood glucose] >28 mM). Intriguingly, the positive inotropic effects of HNO were significantly enhanced in diabetic rat hearts. Further, progressive attenuation of soluble guanylyl cyclase (sGC) contribution to myocardial NO⢠responses occurred with increasing severity of diabetes. Nevertheless, activation of sGC by HNO remained intact in the myocardium. Innovation: Diabetes is associated with marked attenuation of vascular and myocardial effects of NO and NO donors, and this NO⢠resistance is circumvented by HNO, suggesting potential therapeutic utility for HNO donors in cardiovascular emergencies in diabetics. Conclusion: These results provide the first evidence that NO⢠resistance occurs in diabetic hearts, and that HNO largely circumvents this problem. Further, the positive inotropic and lusitropic effects of HNO are enhanced in a severely diabetic myocardium, a finding that warrants further mechanistic interrogation. The results support a potential role for therapeutic HNO administration in acute treatment of ischemia and/or heart failure in diabetics.
Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetic Cardiomyopathies/metabolism , Nitric Oxide/metabolism , Nitrogen Oxides/metabolism , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetic Cardiomyopathies/etiology , Guanylate Cyclase/metabolism , Male , Myocardial Contraction/drug effects , Rats , Streptozocin , Vasodilation/drug effectsABSTRACT
BACKGROUND AND PURPOSE: Arterial stiffness, a characteristic feature of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti-inflammatory protein annexin-A1 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin-A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin-A1 in diabetes-induced remodelling of mouse mesenteric vasculature. EXPERIMENTAL APPROACH: Insulin-resistance was induced in male mice (AnxA1+/+ and AnxA1-/- ) with the combination of streptozotocin (55mg/kg i.p. x 3 days) with high fat diet (42% energy from fat) or citrate vehicle with normal chow diet (20-weeks). Insulin-deficiency was induced in a separate cohort of mice using a higher total streptozocin dose (55mg/kg i.p. x 5 days) on chow diet (16-weeks). At study endpoint, mesenteric artery passive mechanics were assessed by pressure myography. KEY RESULTS: Insulin-resistance induced significant outward remodelling but had no impact on passive stiffness. Interestingly, vascular stiffness was significantly increased in AnxA1-/- mice when subjected to insulin-resistance. In contrast, insulin-deficiency induced outward remodelling and increased volume compliance in mesenteric arteries, regardless of genotype. In addition, the annexin-A1 / formyl peptide receptor axis is upregulated in both insulin-resistant and insulin-deficient mice. CONCLUSION AND IMPLICATIONS: Our study provided the first evidence that endogenous AnxA1 may play an important vasoprotective role in the context of insulin-resistance. AnxA1-based therapies may provide additional benefits over traditional anti-inflammatory strategies for reducing vascular injury in diabetes.
Subject(s)
Annexin A1 , Insulin Resistance , Animals , Inflammation , Insulin , Male , Mice , Receptors, Formyl Peptide/metabolismABSTRACT
BACKGROUND AND PURPOSE: Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI2 ) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium-derived vasoconstriction has never been investigated. We tested the hypothesis that short-term relaxin treatment mitigates endothelium-derived vasoconstriction in spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH: Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L-1 sodium acetate) or relaxin (13.3 µg·kg-1 ·hr-1 ) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium-dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC-MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively. KEY RESULTS: Relaxin treatment ameliorated hypertension-induced endothelial dysfunction by increasing NO-dependent relaxation and reducing endothelium-dependent contraction. Notably, short-term relaxin treatment up-regulated mesenteric PGI2 receptor (IP) expression, permitting PGI2 -IP-mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension-induced increase in prostanoid-producing enzymes and reduction in PGI2 -evoked contractions. CONCLUSIONS AND IMPLICATIONS: Relaxin has region-dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium-derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium-derived vasoconstriction including hypertension.
Subject(s)
Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Hypertension/drug therapy , Hypertension/metabolism , Relaxin/therapeutic use , Vasoconstriction/drug effects , Animals , Dose-Response Relationship, Drug , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Relaxin/pharmacology , Vasoconstriction/physiologyABSTRACT
Cardiovascular disease is the most common cause of mortality worldwide, accounting for almost 50% of all deaths globally. Vascular endothelial dysfunction and fibrosis are critical in the pathophysiology of cardiovascular disease. Relaxin, an insulin-like peptide, is known to have beneficial actions in the cardiovascular system through its vasoprotective and anti-fibrotic effects. However, relaxin has several limitations of peptide-based drugs such as poor oral bioavailability, laborious, and expensive to synthesize. This review will focus on recent developments in relaxin mimetics, their pharmacology, associated signalling mechanisms, and their therapeutic potential for the management and treatment of cardiovascular disease.
Subject(s)
Cardiovascular Diseases/drug therapy , Peptide Fragments/therapeutic use , Relaxin/therapeutic use , Animals , Biomimetics , HumansABSTRACT
BACKGROUND: Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality worldwide. Although predictive multiparametric screening is being developed, it is not applicable to nulliparous women, and is not applied to low-risk women. As PE is considered a heterogenous disorder, it is unlikely that any single multiparametric screening protocol containing a small group of biomarkers could have the required accuracy to predict all PE subgroups. Given the etiology of PE is complex and not fully understood, it begs the question, whether the search for biomarkers based on the predominant view of impaired placentation involving factors predominately implicated in angiogenesis and inflammation, has been too limiting. Here we highlight the enormous potential of state-of-the-art, high-throughput proteomics, to provide a comprehensive and unbiased approach to biomarker identification. METHODS AND FINDINGS: Our literature search identified 1336 articles; after review, 45 studies with proteomic data from PE women that were eligible for inclusion. From 710 proteins with altered abundance, we identified 13 common circulating proteins, some of which had not been previously considered as prospective biomarkers of PE. An additional search of the literature for original publications testing any of the 13 common proteins using non-proteomic techniques was also undertaken. Strikingly, 9 of these common proteins had been independently evaluated in PE studies as potential biomarkers. CONCLUSION: This study highlights the potential of using high-throughput data sets, which are comprehensive and without bias, to identify a profile of proteins that may improve predictions of PE and understanding of its etiology. We bring to the attention of the medical and research communities that the strengths and advantages of using data from high-throughput studies for biomarker discovery would be increased dramatically, if first and second trimester samples were collected for proteomics, and if standardized guidelines for patient reporting and data collection were implemented.
Subject(s)
Biomarkers/analysis , Pre-Eclampsia/diagnosis , Proteome/analysis , Proteomics , Databases, Factual , Female , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/metabolism , Humans , Pre-Eclampsia/metabolism , Pregnancy , Pregnancy Trimester, ThirdABSTRACT
BACKGROUND: Preeclampsia is a major complication of pregnancy with no medical treatment. It is associated with placental oxidative stress, hypoxia and inflammation leading to soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion and reduced placental growth factor (PlGF). This results in widespread endothelial dysfunction causing hypertension and multisystem organ injury. Sulfasalazine is an anti-inflammatory and antioxidant medication used to treat autoimmune disease. Importantly, it is safe in pregnancy. We examined the potential of sulfasalazine to quench antiangiogenic factors and endothelial dysfunction and increase angiogenic factor secretion. METHODS: We performed functional experiments using primary human pregnancy tissues to examine the effects of sulfasalazine on sFlt-1, sENG and PlGF secretion. Sulfasalazine is known to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and upregulate heme-oxygenase 1 (HO-1) thus we explored the effect of these transcription factors on sFlt-1 secretion from human cytotrophoblasts. We examined the ability of sulfasalazine to reduce key markers of endothelial dysfunction and dilate whole blood vessels. FINDINGS: We demonstrate sulfasalazine administration reduces sFlt-1 and sENG and upregulates PlGF secretion from human placental tissues. Furthermore sulfasalazine mitigates endothelial dysfunction in several in vitro/ex vivo assays. It enhanced endothelial cell migration and proliferation, promoted blood vessel dilation (vessels obtained from women at caesarean section) and angiogenic sprouting from whole blood vessel rings. The effect of sulfasalazine on the secretion of sFlt-1 was not mediated through either the NFkB or HO-1 pathways. INTERPRETATION: We conclude that sulfasalazine reduces sFlt-1 and sENG secretion and endothelial dysfunction and upregulates PlGF. Sulfasalazine has potential to treat or prevent preeclampsia and warrants investigation in clinical trials. FUNDING: This work was funded by The National Health and Medical Research Council of Australia (NHMRC; #1048707, #1046484. #1101871, #1064845), an Arthur Wilson RANZCOG scholarship and a Norman Beischer Medical Research Foundation grant. FB was supported by a NHMRC Early Career Fellowship (NHMRC #1142636). NJH was supported by a CR Roper Research Fellowship. The NHMRC provided salary support (#1136418 to ST #1062418 to TKL, #1064845 to SS). The funders had no role in study design, data collection, analysis, decision to publish or the preparation of the manuscript.
Subject(s)
Placenta Growth Factor/metabolism , Sulfasalazine/pharmacology , Up-Regulation/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Endoglin/genetics , Endoglin/metabolism , Female , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Human Umbilical Vein Endothelial Cells , Humans , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Placenta/cytology , Placenta Growth Factor/genetics , Pre-Eclampsia/pathology , Pregnancy , RNA Interference , RNA, Small Interfering/metabolism , Trophoblasts/cytology , Trophoblasts/drug effects , Trophoblasts/metabolism , Vascular Endothelial Growth Factor Receptor-1/genetics , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
Dementia is an increasingly recognised medical condition which, towards its later stages, leads to the manifestation of symptoms that often require palliation. Hospice admission for patients with dementia has been shown to increase caregiver satisfaction. Yet, admission can be harmful for the patient. This feature follows the case of one patient, Mr Smith, who was admitted to Royal Trinity Hospice (RTH) for symptom control, along with providing respite for his carers. Shortly into Mr Smith's admission, he became increasingly agitated and was ultimately discharged home. After investigating the cause of early discharge, it was concluded that the newly built, modernised private rooms were in fact very dissimilar to the homes of patients with dementia. Adapting the clinical environment to improve patient and carer satisfaction has been explored in numerous studies. Significant amendments used by hospices and care homes include bold signs and natural lighting to facilitate way-finding, in addition to vintage furnishings to create a sense of familiarity. Taking recent evidence into consideration, RTH designed a new dementia-friendly bay situated on the ground floor of its inpatient unit. Since then, many other patients with dementia have been admitted to the hospice, one being Mr Thomas. Unlike Mr Smith, Mr Thomas was much more relaxed during his admission and his wife commented on how pleased she was with his care. This feature demonstrates the importance of being receptive to feedback and identifying the need for change.
Subject(s)
Caregivers/psychology , Dementia/psychology , Hospice Care/psychology , Patient Acceptance of Health Care/psychology , Adult , Aged , Aged, 80 and over , Female , Hospices , Hospitalization , Humans , Male , Middle AgedABSTRACT
Early maternal vascular adaptations to pregnancy are predominantly driven by changes in vascular tone, reactivity, and remodeling. Failure of the maternal systemic vasculature to adapt sufficiently can lead to serious complications of pregnancy. The hormone relaxin is widely recognized for its contribution to the essential renal and systemic hemodynamic adaptations in early pregnancy through direct actions on the maternal vasculature. Studies in relaxin gene knockout mice revealed that endogenous relaxin is not only a "pregnancy hormone" but has pleiotropic actions in various tissues in males and non-pregnant females. There is strong interest in relaxin's actions in the vasculature and its utility in the treatment of vascular diseases. Relaxin treatment in rodents for 2-5 days or acute intravenous injection enhances endothelium-dependent relaxation and decreases myogenic tone in resistance arteries. These vascular actions are prolonged, even in the absence of circulating relaxin, and are underpinned by the production of endothelium-derived relaxing factors including nitric oxide, endothelium-derived hyperpolarization, and prostacyclin. Relaxin is also capable of remodeling the vascular wall in a variety of blood vessels in disease conditions. Lessons learned in pregnancy research have aided studies investigating the potential therapeutic potential of relaxin in cardiovascular disease.
Subject(s)
Pregnancy , Relaxin/physiology , Animals , Blood Vessels/drug effects , Cardiovascular Diseases/drug therapy , Female , Hemodynamics/drug effects , Humans , Male , Relaxin/deficiency , Relaxin/therapeutic use , Vasodilation/drug effectsABSTRACT
Preeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear. Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby. Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia.
ABSTRACT
Cardiovascular complications are the major cause of mortality in patients with diabetes. This is closely associated with both macrovascular and microvascular complications of diabetes, which lead to organ injuries in diabetic patients. Previous studies have consistently demonstrated the beneficial effects of relaxin treatment for protection of the vasculature, with evidence of antioxidant and anti-remodeling actions. Relaxin enhances nitric oxide, prostacyclin and endothelium-derived hyperpolarization (EDH)-type-mediated relaxation in various vascular beds. These effects of relaxin on the systemic vasculature, coupled with its cardiac actions, reduce pulmonary capillary wedge pressure and pulmonary artery pressure. This results in an overall decrease in systemic and pulmonary vascular resistance in heart failure patients. The anti-fibrotic actions of relaxin are well established, a desirable property in the context of diabetes. Further, relaxin ameliorates diabetic wound healing, with accelerated angiogenesis and vasculogenesis. Relaxin-mediated stimulation of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1-α, as well as regulation of metalloproteinase expression, ameliorates cardiovascular fibrosis in diabetic mice. In the heart, relaxin is a cardioprotective molecule in several experimental animal models, exerting anti-fibrotic, anti-hypertrophy and anti-apoptotic effects in diabetic pathologies. Collectively, these studies provide a foundation to propose the therapeutic potential for relaxin as an adjunctive agent in the prevention or treatment of diabetes-induced cardiovascular complications. This review provides a comprehensive overview of the beneficial effects of relaxin, and identifies its therapeutic possibilities for alleviating diabetes-related cardiovascular injury.