The role of red blood cells in cardiac and endothelial dysfunction in cardiometabolic disease

Abstract

Background: Cardiometabolic disease, which includes the combination of cardiovascular disease, especially coronary artery disease and type 2 diabetes (T2D), is a major health problem and cause of mortality worldwide. ST-elevation myocardial infarction (STEMI) occurs when coronary arteries are occluded and is regarded as a life-threatening disorder. In these situations, both cardiac and endothelial function are impaired but specific treatment to alleviate the dysfunction is lacking which is partially due to that the underlying mechanisms remain unclear. Red blood cells (RBCs) have for long been considered as passive transporters of respiratory gases. Emerging evidence suggests that RBCs are critically involved in physiological cardiovascular regulation by exporting nitric oxide (NO) bioactivity and adenosine triphosphate, especially under hypoxic and ischemic conditions. It has been further suggested that dysfunctional RBCs may act as mediators of cardiovascular injury under pathological conditions. However, the role of RBCs in patients with cardiovascular disease associated with T2D has not been explored.

Purpose: The purpose of this thesis was to investigate the role of RBCs in the development of cardiac and endothelial dysfunction in cardiometabolic disease.

Methods and results: In Study I, RBCs from both patients and mice with T2D were given to isolated Langendorff-perfused hearts from mice or rats ex vivo at the onset of myocardial ischemia followed by reperfusion. The post-ischemic cardiac recovery was impaired and infarct size was increased via a mechanism depending on upregulated RBC-arginase which led to increased formation of reactive oxygen species by the NO-producing enzyme NO synthase. In Study II, RBCs from patients with T2D under poor or improved glycemic control were given to Langendorff-perfused hearts or incubated with rat aorta. Improvement in glycemic control attenuated cardiac but not endothelial dysfunction induced the by RBCs. RBC-arginase activity was reduced following improvement in glycemic control. Inhibition of arginase attenuated the negative effect of RBCs on cardiac function irrespective of the glycemic control. In Study III, stimulation of the NO receptor soluble guanylyl cyclase (sGC) in RBCs from patients with T2D attenuated the impairment in post-ischemic cardiac recovery and the increase in infarct size induced by the RBCs. The supernatant collected from RBCs incubated with the sGC stimulator also improved post-ischemic cardiac recovery and reduced infarct size. sGC stimulation in RBCs increased export of cyclic guanosine monophosphate (cGMP) to the supernatant and phosphorylation of cardiac vasodilator phosphoprotein as a marker of activation of cGMP-dependent protein kinase G. This suggests that cGMP may be the cardioprotective mediator from the RBCs. In Study IV, RBCs from patients with STEMI protected against post-ischemic cardiac dysfunction and reduced infarct size in isolated hearts subjected to ischemia-reperfusion. Mechanistic studies indicated that the beneficial effect was mediated via increased NO-sGC signaling in the RBCs mediated by the purinergic P2Y13 receptor.

Conclusions: The present studies importantly increase our understanding of the role of RBC function in cardiometabolic disease. The RBC represents a novel mediator of cardiac and endothelial dysfunction and a potentially important therapeutic target in patients with T2D and STEMI.