The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications

Abstract

Diabetes mellitus is a major debilitating disease whose global incidence is progressively increasing with currently over 463 million adult sufferers and this figure will likely reach over 700 million by the year 2045. It is the complications of diabetes such as cardiovascular, renal, neuronal and ocular dysfunction that lead to increased patient morbidity and mortality. Of these, cardiovascular complications that can result in stroke and cardiomyopathies are 2- to 5-fold more likely in diabetes but the underlying mechanisms involved in their development are not fully understood. Emerging research suggests that members of the Epidermal Growth Factor Receptor (EGFR/ErbB/HER) family of tyrosine kinases can have a dual role in that they are beneficially required for normal development and physiological functioning of the cardiovascular system (CVS) as well as in salvage pathways following acute cardiac ischemia/reperfusion injury but their chronic dysregulation may also be intricately involved in mediating diabetes-induced cardiovascular pathologies. Here we review the evidence for EGFR/ErbB/HER receptors in mediating these dual roles in the CVS and also discuss their potential interplay with the Renin-Angiotensin-Aldosterone System heptapeptide, Angiotensin-(1-7), as well the arachidonic acid metabolite, 20-HETE (20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid). A greater understanding of the multi-faceted roles of EGFR/ErbB/HER family of tyrosine kinases and their interplay with other key modulators of cardiovascular function could facilitate the development of novel therapeutic strategies for treating diabetes-induced cardiovascular complications.

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

“…Furthermore, recent studies indicate that EGFR inhibition has a protective effect on cardiomyocytes under hypoxic conditions, i.e., after myocardial infarctions (Heliste et al, 2021). It seems that like in other tissues, EGFR signaling is tightly controlled in the heart, and due to its double role and the multitude of its downstream effectors, any alterations in EGFR signaling can have severe effects on heart function (Shraim et al, 2021, Forrester et al, 2016).…”

MultiCens: Multilayer network centrality measures to uncover molecular mediators of tissue-tissue communication

“…While a few genes (yellow background) from our predictions are already present in our ground truth HGv1, there are other genes (green background) not present in HGv1 but whose associations are confirmed by the high PubMed-based similarity scores with at least one of the hormone-related terms. For insulin for example, we obtain two such out-of-ground-truth genes: LRRC8 , which has been found to enhance insulin secretion in pancreatic β -cells in a recent study [26], with later studies confirming its role in insulin resistance and glucose resistance [27]; similarly, EGFR gene is known to mediate diabetes-induced microvascular dysfunction [28].…”

Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma

“…In OSCC tissues, the relationship between EGFR overexpression and poor survival of patients has been repeatedly reported ( 19 , 20 ). The expression of EGFR mediates systemic complications of T2DM that affect the heart, kidneys, and eyes ( 21 ). High-glucose culture of pancreatic cancer cell lines increases the expression of EGF, which then activates EGFR ( 18 ).…”