Dysregulation of TRPV4, eNOS and caveolin-1 contribute to endothelial dysfunction

The streptozotocin rat model of diabetes

Significance

With an estimated 450 million diabetes patients worldwide in 2020, Diabetes mellitus has reached a pandemic proportion and represents a major unmet medical need. Various organs and tissues are damaged by prolonged exposure to high blood sugar levels, which leads to diabetes‐related complications such as cardiovascular disease, nephropathy, neuropathy, retinopathy and lower extremity amputation. These complications impact the quality of life of patients with diabetes and have become economic and healthcare burdens in many countries.

A common complication in diabetes is endothelial dysfunction, an impairment of endothelium-dependent vasorelaxation that makes diabetics vulnerable to end-organ damage and limb infections. TRPV4 is a member of the transient receptor potential (TRP) ion channel family known to make important contributions to vascular tone. The expression of TRPV4 has been shown by various pharmacological studies to be a functional component of endothelial cells in dilating rat aortic rings and carotid artery, mesenteric arteries and aortic myocytes. Studies have also provided evidence that suggest that one of the contributors to the vascular dysfunction in diabetes is a dysfunction in TRPV4. Another important integral membrane protein is Caveolin-1, it is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance.

Another important signaling molecule that play an essential role in maintaining vascular function is nitric oxide which is produced by endothelial cells through the endothelial nitric oxide synthase (eNOS) and plays a major role for many of these endothelial functions and indeed decreased NO production and bioavailability largely contribute to endothelial dysfunction in diabetes

There is compelling evidence that endothelial dysfunction serves as a key event in the development and progression of diabetic vascular complications. To look at these important signaling proteins in diabetes, a new published research paper in the European Journal of Pharmacology, Researchers from the University of Hertfordshire in the United Kingdom: Dr. Yousif Shamsaldeen, Dr. Lisa Lione and Dr. Christopher Benham investigated the association between reduced expression of TRPV4, eNOS and caveolin-1 and type 1 diabetic endothelial dysfunction. They showed that a reduced expression of TRPV4, eNOS and caveolin-1 was indeed associated with endothelial dysfunction in diabetic disease model in rats.

They used a well-accepted animal disease model to study diabetes where they induced diabetes pheynotype in rats by injection of Streptozotocin (STZ). The STZ-treated diabetic rats were found to have endothelial dysfunction with impaired muscarinic-induced vasorelaxation and TRPV4-induced vasorelaxation. There was also a significant reduction in endothelial cholinergic and TRPV4-induced vasorelaxation in the aortic rings of the STZ-treated rats.The primary aortic endothelial cells from STZ-treated rats were found to have reduced TRPV4 mediated calcium signaling, which was reversed with insulin treatment. Likewise, there was a reduced expression of TRPV4, caveolin-1 and eNOS in the primary aortic endothelial cells of STZ-diabetic rats which was also reversed by insulin treatment.

The study is the first of its kind to explore the three endothelial signalling components, TRPV4, caveolin-1 and eNOS and endothelial dysfunction; together in a single type 1 diabetes model. When the authors treated the diabetic rats with Insulin, they observed the functional restoration of TRPV4 and restored expression of three endothelial signalling components.

The study demonstrated successfully the direct and specific beneficial effects insulin on endothelial function in insulin-dependent diabetes, irrespective of any change in glucose levels. They recommend further studies to be conducted to examine the effectiveness of insulin in restoring the functions and expression of these endothelial signalling components.

About the author

Dr Chris Benham
Head of Pharmacology
School of Life and Medical Sciences
University of Hertfordshire

Chris Benham is an electrophysiologist with 40 years experience working on ion channels in academia and in the pharmaceutical industry. His early academic interests were in smooth muscle ion channel function developing patch clamp and Ca imaging techniques to investigate Ca permeable ion channels, and this broadened to ion channel drug discovery in the CNS with a continuing focus on calcium permeable ion channels. At GSK he was instrumental in setting up and developing the companies interest in the Transient Receptor Potential (TRP) family of ion channels. It is perhaps a reflection of the challenges and persistence required for drug discovery in new areas, that 25 years later GSK is still working on these targets with molecules in the clinic. Since joining the University of Hertfordshire in 2006, he has maintained this interest examining changes in TRP channel function that occur in in vitro and in vivo models of diabetes. Changes in function in TRPV1, TRPA1 and TRPV4 may underlie some of the pathophysiological changes that occur in sensory, cardiovascular and gastrointestinal systems as a consequence of diabetes.

About the author

Lisa Lione is an Associate Professor in Translational Pharmacology research at the University of Hertfordshire (UH). Lisa’s research is collaborative combining her specialised in vivo skills with industry experience in drug discovery and translational science. Since joining UH in 2008 Lisa has led a translational pharmacology research programme centred on understanding novel pharmacological mechanisms that drive complications of diabetes in mammalian models. Lisa currently supervises 3 PhD students at UH funded by QR and industry. Lisa is particularly interested in the promotion and sharing of best practice in animal welfare, ethics and the 3Rs (she is the University representative for concordat on openness of animal research and a member of the national NC3Rs studentship assessment panel) as well as raising awareness of drugs education in schools and universities (she is an expert advisory panel member for Mentor UK, a school governor and external examiner at the University of Central Lancashire).

About the author

Dr Yousif Shamsaldeen
Postdoctoral Researcher in Molecular and Clinical Sciences
St. George’s University of London

Yousif Shamsaldeen is a pharmacist and pharmacologist. His research interest in the field of pharmacology started with his MSc research project at the University of Hertfordshire where his research focused on Akt role in stem cell differentiation into cardiomyocytes. His research experience was then broadened as his PhD project at the University of Hertfordshire focused on endothelial dysfunction in diabetes where he covered a wide range of pharmacological techniques including Ca²⁺ imaging, Western blotting, and confocal microscopy. His main research interest focused on endothelial TRPV4 calcium channels dysfunction and downregulation in diabetes. His experience in the field of pharmacology was widened by conducting part of his PhD at King’s College under the supervision and collaboration with Professor Stuart Bevan. Such an extensive experience in the field of pharmacology has supported him to join the University of Bath immediately after completing his PhD. At the University of Bath, he worked as a postdoctoral researcher where his research focused on investigating the role of NLRPF3 inflammasome in age-related macular degeneration. At the University of Bath, Yousif applied his experience in fulfilling the requirements to securing a research grant for the University within six months of joining the University of Bath. He moved afterwards to the University of Bristol as a senior postdoctoral researcher. At the University of Bristol, Yousif conducted a research in the field of atrial fibrillation and ion channels.

His work included collecting human samples from cardiac surgery unit from Bristol Heart Institute and conducting patch clamp and immunocytochemistry studies through which he published a research paper in the field of atrial fibrillation and calcium activated potassium channels (SKca). During COVID-19 pandemic, Yousif worked as a hospital pharmacist in Kuwait, where he worked in clinical practice and invested his research experience to publish clinical studies. Yousif then has moved back to the UK to join St. George’s University of London where he has restarted his academic and research career as a postdoctoral researcher in the field of cardiovascular pharmacology.

Reference

Shamsaldeen YA, Lione LA, Benham CD. Dysregulation of TRPV4, eNOS and caveolin-1 contribute to endothelial dysfunction in the streptozotocin rat model of diabetes. Eur J Pharmacol. 2020 Dec 5;888:173441.

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