FTY720 Protects Cardiac Microvessels of Diabetes: A Critical Role of S1P1/3 in Diabetic Heart Disease

Abstract

Background: Diabetes is associated with an increased risk of cardiac microvascular disease. The mechanisms by which this damage occurs are unknown. However, research suggests that signaling through the sphingosine-1-phosphates receptor 1 and 3 (S1P1/3) by FTY720, a sphiongolipid drug that is structually similar to SIP, may play a role in the treatment on cardiac microvascular dysfunction in diabetes. We hypothesized that FTY720 might exert the cardioprotective effects of S1P1 and S1P3 viaprotein kinase C-beta (PKCβ II) signaling pathway. Methodology/Principal Findings: Transthoracic echocardiography was performed to detect the change of cardiac function. Scanning and transmission electron microscope with lanthanum tracer were used to determine microvascular ultrastructure and permeability in vivo. Apoptosis was detected by TUNEL and CD31 dual labeling in paraffin-embedded sections. Laser capture miscrodissection was used to assess cardiac micovascular endothelial cells (CMECs) in vivo. RT-PCR and Western blot analysis were used to determine the mRNA levels and protein expression of S1P1, S1P3, and PKCβ II. In the diabetic rats vs. controls, cardiac capillaries showed significantly higher density; CD31 positive endothelial cells were significantly reduced; the apoptosis index of cardiac endothlial cells was significantly higher. And FTY720 could increase the expressional level of S1P1 and boost S1P3 trasnslocation from membrane to nuclear, then ameliorate cardiac microvascular barrier impairment and pathologic angiogenesis induced by diabetes. In addition, overexpression of PKCβ II significantly decreased the protective effect of FTY720. Conclusions: Our study represents that the deregulation of S1P1 and S1P3 is an important signalresponsible for cardiac microvascular dysfunction in diabetes. FTY720 might be competent to serve as a potential therapeutic approach for diabetic heart disease through ameliorating cardiac microvascular barrier impairment and pathologic angiogenesis, which might be partly dependent on PKCβII-mediated signaling pathway.

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

“…However, in one recent study, attenuation of retinal vascular leakages after a 12-week fingolimod treatment in streptozotocin (STZ)-induced diabetic rats has been reported [63]. Moreover, there are several works underlining that long-term treatment with fingolimod does not impair endothelial barrier function [64,65], which might be explained by the fact that, despite membrane downregulation, the internalized S1P 1 receptor still actuates signaling pathways [66] or that this function does not depend on the S1P 1 receptor at all [67]. Conversely, it has been shown that long-term treatment with fingolimod worsens vascular leakage in bleomycin-induced lung injury [68].…”

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

“…It also acts as a potent S1PR agonist, preferentially to S1PR1, and to a lesser extent, S1PR3 [235], thereby mimicking S1P responses. In relation to the cardiovascular system, FTY720 blocks chronic inflammation, protects both the macrovasculature and microvasculature from damage [233,234,236], and ameliorates cardiac remodeling postmyocardial infarction [103]. The administration of FTY720 has been reported to prevent the formation of fibrosis by stimulating anti-inflammatory and anti-oxidant mechanisms in the myocardium [237].…”

Switching the Sphingolipid Rheostat in the Treatment of Diabetes and Cancer Comorbidity from a Problem to an Advantage

“…Although there are several studies and reviews emphasising the importance of SphK1/S1P in cardioprotection (as mentioned above), elevated SphK1/S1P levels have also been associated with the negative effects of cardiovascular diseases linked to diabetes. For example, in one study SphK1 inhibition ameliorated angiotensin II-induced acute hypertension [ 76 ] and in another study deregulation of specific S1Ps played a role in cardiac microvascular dysfunction [ 77 ]. A growing list of adverse diabetic complications is believed to be involved with high levels of SphK1/S1P expression including neuropathy [ 36 , 78 , 79 ], retinopathy [ 80 – 84 ], nephropathy [ 85 ], and cancer [ 5 , 6 , 8 ].…”