Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice

Abstract

Diabetes mellitus is characterized by changes in endothelial cells that alter monocyte recruitment, increase classic (M1-type) tissue macrophage infiltration and lead to self-sustained inflammation. Our and other groups recently showed that chronic inhibition of phosphodiesterase-5 (PDE5i) affects circulating cytokine levels in patients with diabetes; whether PDE5i also affects circulating monocytes and tissue inflammatory cell infiltration remains to be established. Using murine streptozotocin (STZ)-induced diabetes and in human vitro cell-cell adhesion models we show that chronic hyperglycemia induces changes in myeloid and endothelial cells that alter monocyte recruitment and lead to self-sustained inflammation. Continuous PDE5i with sildenafil (SILD) expanded tissue anti-inflammatory TIE2-expressing monocytes (TEMs), which are known to limit inflammation and promote tissue repair. Specifically, SILD: 1) normalizes the frequency of circulating pro-inflammatory monocytes triggered by hyperglycemia (53.7 ± 7.9% of CD11b+Gr-1+ cells in STZ vs. 30.4 ± 8.3% in STZ+SILD and 27.1 ± 1.6% in CTRL, P<0.01); 2) prevents STZ-induced tissue inflammatory infiltration (4-fold increase in F4/80+ macrophages in diabetic vs. control mice) by increasing renal and heart anti-inflammatory TEMs (30.9 ± 3.6% in STZ+SILD vs. 6.9 ± 2.7% in STZ, P <0.01, and 11.6 ± 2.9% in CTRL mice); 3) reduces vascular inflammatory proteins (iNOS, COX2, VCAM-1) promoting tissue protection; 4) lowers monocyte adhesion to human endothelial cells in vitro through the TIE2 receptor. All these changes occurred independently from changes of glycemic status. In summary, we demonstrate that circulating renal and cardiac TEMs are defective in chronic hyperglycemia and that SILD normalizes their levels by facilitating the shift from classic (M1-like) to alternative (M2-like)/TEM macrophage polarization. Restoration of tissue TEMs with PDE5i could represent an additional pharmacological tool to prevent end-organ diabetic complications.

Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol

“…In line with these findings, relevant signs of ventricular dysfunction and the overt DCM phenotype occur in this model of late diabetes, as reported in previous studies [12,22]. Although we cannot exclude that other mechanisms, besides humoral changes, are involved [50], our data confirm that prolonged hyperglycemia induces M1 macrophage infiltration which is known to be associated with reduced survival and greater tissue damage [28,51]. RSV treatment promoted the M2 macrophage phenotype, resulting in a significant reduction in the M1/M2 macrophage ratio, accompanied by a recovery of cardiomyocyte ultrastructural properties.…”

Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): How do they work?

“…Chronic proinflammatory M1-type macrophage infiltration has been reported in insulin resistance linking diabetes to vascular disease: defective remodeling and repair following injury in diabetes are the final steps of an impaired control of inflammation and tissue damage. A recent study on murine streptozotocin-induced diabetes and in human vitro cell-cell adhesion models showed that sildenafil treatment (1.6 mg/kg/day for 3/6 weeks) was able to restore the endothelial cells alteration and proinflammatory status, hyperglycemia related, by reducing vascular inflammatory proteins, promoting tissue protection, and lowering monocyte adhesion to human endothelial cells [63].…”

Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

“…PDE5 inhibitors (PDE5is) may have an active role in the management of DN13 by reducing glomerulosclerosis and proteinuria and improving vascular inflammation and podocyte count in experimental diabetes models14151617. These findings, together with the modulation of inflammatory1418 and angiogenic mediators, and endothelial function1920 in murine and human models, support the use of PDE5i to prevent complications of the diabetic kidney.…”