Objectives Tissue kallikrein is a major kinin-forming enzyme involved in artery and kidney functions. Urinary tissue kallikrein activity (UKLKa) reflects renal tissue kallikrein activity and depends on Na and K intake, and genetic factors, especially the tissue kallikrein-inactivating polymorphism, R53H. The effect of these factors on the level of kinin peptides is, however, not known. Moreover, a circulating form of tissue kallikrein is present in human plasma but its origin and regulation are unknown. Methods We used a crossover study to investigate UKLKa, plasma tissue kallikrein (pTK), and urinary kallidin peptides and metabolites (Uki) in 10 R53H and 30 R53R normotensive male subjects randomly assigned to either a 1-week low Na–high K or a high Na–low K diet. Results UKLKa was 50–60% lower in R53H than R53R subjects and was increased by the low Na–high K diet. pTK was also 45–55% lower in R53H than R53R subjects and was increased by the low Na–high K diet. Uki was slightly but significantly higher under the low Na–high K than the high Na–low K diet, but did not differ between genotypes. Conclusion These observations indicate that pTK levels are genetically determined and regulated by Na and K diet, in parallel with UKLKa; this suggests that circulating tissue kallikrein originates mainly from the kidney, and can contribute to circulatory adaptation to dietary ions. Uki is influenced by the Na and K diet, suggesting that kinins participate in renal adaptation to ion intake, but do not quantitatively reflect tissue kallikrein activity in urine, or presumably, in the kidney.
Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH 2 ) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH 2 ) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.
Diabetes mellitus is associated with macro- and micro-angiopathy, leading to increased risk of peripheral ischemia. In the present study, we have characterized the microvascular phenotype at the level of limb muscles and the spontaneous angiogenesis response to surgically-induced unilateral limb ischemia in a murine model of type-2 diabetes, the obese C57BL/KsOlaHsd-Lepr(db/db) mice (Lepr(db/db)), and in non-diabetic heterozygous Lepr(db/+). Wild type C57BL mice (WT) were used as controls. The basal microvascular phenotype was determined in mice aged 3 or 5 months, while the response to limb ischemia was studied only in 5-month old mice. Moreover, in 5-month old ischemic Lepr(db/db) and Lepr(db/+), we have tested the therapeutic potential of local angiogenesis gene therapy with human tissue kallikrein (hTK) or constitutively-activated Akt kinase (Myr-Akt). We found that in the muscles of 3- or 5-month old Lepr(db/db), apoptosis of endothelial cells was enhanced and the densities of capillary and arteriole were reduced. Arterioles of Lepr(db/db) showed hypertrophic remodelling and, occasionally, lumen occlusion. Following ischemia, Lepr(db/db) showed a defective reparative angiogenesis in ischemic muscle, delayed blood flow recovery, and worsened clinical outcome as compared with controls. Five-month old Lepr(db/+) displayed an increase in endothelial cell apoptosis under basal conditions, while capillary and arteriole densities were normal. Lepr(db/+) mounted a proper reparative angiogenesis response to limb ischemia and regained blood flow to the ischemic limb, regularly. Local gene therapy with hTK or Myr-Akt induced angiogenesis in ischemic muscles of Lepr(db/+) and Lepr(db/db). However, in the Lepr(db/db) neither gene therapy approach improved the blood flow recovery and the clinical outcome from ischemia. In contrast, either hTK or Myr-Akt gene transfer improved the post-ischemic recovery of Lepr(db/+). Type-2 diabetes has a negative impact on the basal microvascular phenotype and severely impairs post-ischemic recovery of limb muscles. Gene therapy-induced stimulation of neovascularization might not suffice as a sole therapeutic strategy to combat type-2 diabetes-related vascular complications. In type-2 diabetic patients, therapeutic angiogenesis may need to be further optimized before being recommended for clinical applications.
An aneurysm is a local dilatation of a vessel wall which is >50% its original diameter. Within the spectrum of cardiovascular diseases, aortic aneurysms are among the most challenging to treat. Most patients present acutely after aneurysm rupture or dissection from a previous asymptomatic condition and are managed by open surgical or endovascular repair. In addition, patients may harbour concurrent disease contraindicating surgical intervention. Collectively, these factors have driven the search for alternative methods of identifying, monitoring and treating aortic aneurisms using less invasive approaches. Non-coding RNA (ncRNAs) are emerging as new fundamental regulators of gene expression. The small microRNAs have opened the field of ncRNAs capturing the attention of basic and clinical scientists for their potential to become new therapeutic targets and clinical biomarkers for aortic aneurysm. More recently, long ncRNAs (lncRNAs) have started to be actively investigated, leading to first exciting reports, which further suggest their important and yet largely unexplored contribution to vascular physiology and disease.
Abstract COronaVIrus Disease 19 (COVID-19) is caused by the infection of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are respiratory, many patients also display acute myocardial injury and chronic damage to the cardiovascular system. Understanding both direct and indirect damage caused to the heart and the vascular system by SARS-CoV-2 infection is necessary to identify optimal clinical care strategies. The homeostasis of the cardiovascular system requires a tight regulation of the gene expression, which is controlled by multiple types of RNA molecules, including RNA encoding proteins (messenger RNAs) (mRNAs) and those lacking protein-coding potential, the noncoding-RNAs. In the last few years, dysregulation of noncoding-RNAs has emerged as a crucial component in the pathophysiology of virtually all cardiovascular diseases. Here we will discuss the potential role of noncoding RNAs in COVID-19 disease mechanisms and their possible use as biomarkers of clinical use.
steroidal anti-inflammatory drugs (NSAIDs), cardiac biomarkers, ECG, echocardiography, cardiac MRI, chest CT, invasive cardiac procedures, and cardiac complications.Furthermore, cardiac outcomes during admission at 7 and 30 days are collected.A specification on all variables included can be found in the REDCap Codebook on our website.All patients with a highly suspected or proven infection with SARS-CoV-2 are eligible for inclusion in CAPACITY-COVID.We strongly encourage multidisciplinary collaborative efforts to collect the data, in order to increase the coverage of inclusion across various departments involved in the care of these patients.In the short term, the primary focus of the consortium will be to develop prognostic models with the collected data.Since the launch of the registry, thus far, 43 of the 71 Dutch hospitals have joined the consortium.Furthermore 19 sites across 10 other countries have expressed their interest to participate.At this moment in time 18 centres have started data collection.We hereby would like to invite other centres to participate in CAPACITY-COVID.To allow a quick set-up of the project for centres that want to participate, we have developed a portfolio of resources, including the study protocol, patient information form, and standard operating procedures that are all freely available.
A bstract : Therapeutic angiogenesis/vasculogenesis represents a new approach to treat patients with ischemic disease not curable with conventional treatment. This review focuses on the rationale and preliminary results of combining stem cell and gene therapy for regenerative medicine. Under disease conditions, impaired neovascularization results from diminished vascular growth factor production and primary dysfunction of endothelial cells and their progenitors. Advances in our ability to genetically manipulate cells ex vivo has provided the technological platform to implement stem cell biology and circumvent the potential hazard of direct gene transfer. Ex vivo engineered endothelial progenitor cells have been used for the treatment of peripheral limb ischemia. The approach eliminates the drawback of immune response against viral vectors and makes feasible repeating the therapeutic procedure in case of injury recurrence. The strategy of using stem cells as vectors for curative agents proved to be of value for the treatment of pulmonary hypertension and thrombosis. Transplantation of neural stem cells genetically modified to secrete nerve growth factor was able to ameliorate the death of striatal projection neurons caused by transient focal ischemia in the adult rat. By a similar approach, engineered neural stem cells might be used for treating neurodegenerative disorders. Therefore, genetic manipulation of stem cells opens new avenues for regenerative medicine.
Inhalation of cold air in guinea pigs increases total pulmonary resistance (Rl), an effect that is mediated by kinins and tachykinins. Bronchoconstriction induced by bradykinin (BK) inhalation in guinea pigs is markedly inhibited by nitric oxide (NO) release from the airway epithelium. We investigated whether endogenous NO modulates the increase in Rl induced by inhalation of cold air. In anesthetized and artificially ventilated guinea pigs pretreated with atropine, cold-air inhalation (13 ° C in the trachea) for 5 min did not increase Rl. Pretreatment with intravenous NG-nitro-l-arginine methyl ester (l-NAME) (but not with its inactive enantiomer, d-NAME) increased Rl, an effect reversed by l-Arg. The increase in Rl induced by cold air after l-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2 -receptor antagonist, HOE 140. After administration of SR 48968, inhalation of cold air reduced baseline airway tone. However, after HOE 140, cold-air inhalation did not affect baseline airway tone. l-NAME exaggerated the bronchoconstriction induced by BK. However, l-NAME did not affect capsaicin-induced bronchoconstriction. BK increased cyclic guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle in vitro, whereas the selective tachykinin NK2-receptor agonist [ β Ala8]neurokinin A (4-10) was without effect. The present data suggest that bronchoconstriction induced by cold-air inhalation and mediated by kinin and tachykinin release is inhibited by endogenous NO, and that kinins, but not tachykinins or cold air alone, release bronchorelaxant NO.
The endothelin (ET) receptor subtype that mediates niric oxide (NO)‐dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea‐pig trachea using a recently developed porphyrinic microsensor was also measured. ET‐1 (1 p M –100 n M ) contracted tracheal tube preparations pretreated with the NO‐synthase inhibitor, L ‐NMMA, and relaxed, in an epithelium‐dependent manner, preparations pretreated with the inactive enantiomer D ‐NMMA. The effect of L ‐NMMA was reversed by L ‐Arg, but not by D ‐Arg. The selective ET B receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 p M –100 n M ) contracted tracheal tube preparations in a similar manner either after treatment with D ‐NMMA or with L ‐NMMA. In the presence of the ET A receptor antagonist, FR139317 (10 μ M ), ET‐1 administration resulted in a contraction that was similar after either L ‐NMMA or D ‐NMMA. In the presence of the ET B receptor antagonist, BQ788 (1 μ M ), ET‐1 relaxed and contracted tracheas pretreated with D ‐NMMA and L ‐NMMA, respectively. Exposure of tracheal segments to ET‐1 (1–1000 n M ) caused a concentration‐dependent increase in NO release that was reduced by L ‐NMMA. IRL1620 (1 μ M ) did not cause any significant NO release. FR139317 (10 μ M ), but not, BQ788 (1 μ M ), inhibited the NO release induced by ET‐1. These results demonstrate that in the isolated guinea‐pig trachea activation of ET B receptors results in a contractile response, whereas activation of ET A receptors cause both a contraction, and an epithelium‐dependent relaxation that is mediated by NO release. British Journal of Pharmacology (1998) 125 , 963–968; doi: 10.1038/sj.bjp.0702174
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