Complex role of RhoA in regulating vascular smooth muscle cell phenotypes in type 2 diabetes

Abstract

The incidence of type 2 diabetes mellitus (T2DM) is growing globally, and the major cause of morbidity and mortality in these patients is the premature development of cardiovascular disease. Consequently, medical interventions, such as coronary artery bypass graft surgery and widespread statin prescriptions, are common in this patient group. Smooth muscle cells are the major structural component of the vascular wall. They play a crucial role in post-bypass recovery to successfully revascularize the heart by switching between differentiated (contractile) and dedifferentiated (synthetic) phenotypes. However, in patients with T2DM, these cells have functional defects that may affect bypass integration. RhoA is a small GTPase that regulates many functions, such as motility and phenotypic regulation of smooth muscle cells. RhoA is dependent upon a stimulus, and it can drive the contractile smooth muscle cell phenotype present in the healthy condition or the (mal)adaptive phenotypes prevalent in disease or in response to injury. We hypothesize that RhoA deregulation plays a major role in vascular complications of T2DM. This protein is deregulated in T2DM smooth muscle cells, which may in part explain the functional defects of smooth muscle tissue and the subsequent failure rate of bypass in these patients. An important consideration in this circumstance is the use of statin therapies because these further inhibit RhoA activity. The effect of inhibition of RhoA activity in patients with T2DM who have a bypass is currently unknown.