The SGLT2 Inhibitor Luseogliflozin Rapidly Normalizes Aortic mRNA Levels of Inflammation-Related but Not Lipid-Metabolism-Related Genes and Suppresses Atherosclerosis in Diabetic ApoE KO Mice

Abstract

Recent clinical studies have revealed the treatment of diabetic patients with sodium glucose co-transporter2 (SGLT2) inhibitors to reduce the incidence of cardiovascular events. Using nicotinamide and streptozotocin (NA/STZ) -treated ApoE KO mice, we investigated the effects of short-term (seven days) treatment with the SGLT2 inhibitor luseogliflozin on mRNA levels related to atherosclerosis in the aorta, as well as examining the long-term (six months) effects on atherosclerosis development. Eight-week-old ApoE KO mice were treated with NA/STZ to induce diabetes mellitus, and then divided into two groups, either untreated, or treated with luseogliflozin. Seven days after the initiation of luseogliflozin administration, atherosclerosis-related mRNA levels in the aorta were compared among four groups; i.e., wild type C57/BL6J, native ApoE KO, and NA/STZ-treated ApoE KO mice, with or without luseogliflozin. Short-term luseogliflozin treatment normalized the expression of inflammation-related genes such as F4/80, TNFα, IL-1β, IL-6, ICAM-1, PECAM-1, MMP2 and MMP9 in the NA/STZ-treated ApoE KO mice, which showed marked elevations as compared with untreated ApoE KO mice. In contrast, lipid metabolism-related genes were generally unaffected by luseogliflozin treatment. Furthermore, after six-month treatment with luseogliflozin, in contrast to the severe and widely distributed atherosclerotic changes in the aortas of NA/STZ-treated ApoE KO mice, luseogliflozin treatment markedly attenuated the progression of atherosclerosis, without affecting serum lipid parameters such as high density lipoprotein, low density lipoprotein and triglyceride levels. Given that luseogliflozin normalized the aortic mRNA levels of inflammation-related, but not lipid-related, genes soon after the initiation of treatment, it is not unreasonable to speculate that the anti-atherosclerotic effect of this SGLT2 inhibitor emerges rapidly, possibly via the prevention of inflammation rather than of hyperlipidemia.

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…In turn, uric acid is another potent activator of the NLRP3 inflammasome in immune cells and of NF‐kB in liver cells . Notably, observations in animal models showed that the anti‐inflammatory effect of SGLT2 inhibitors often converge on the IL‐1 pathway . In this respect, SGLT2 inhibitors could represent the first class of hypoglycaemic drugs that “uncouple” feeding from the associated pro‐inflammatory response.…”

“…For instance, diabetic rats treated with empagliflozin showed decreased inflammation, as evidenced by MCP‐1 downregulation in the rat aorta . Similar results were later reproduced with various T2DM mouse models . However, because control animals were not treated with glucose‐lowering agents, it is not known whether these effects are the result of the specific activity of SGLT2 inhibitors or reflect the effective amelioration of hyperglycaemia, which, per se , fosters LGI .…”

“…54 Similar results were later reproduced with various T2DM mouse models. [55][56][57][58][59] However, because control animals were not treated with glucose-lowering agents, it is not known whether these effects are the result of the specific activity of SGLT2 inhibitors or reflect the effective amelioration of hyperglycaemia, which, per se, fosters LGI. 32,60 An elegant study showed that peritoneal macrophages secrete IL-1β in a glucose-dependent manner in response to feeding and post-prandial glycaemic spikes.…”

“…64,65 Notably, observations in animal models showed that the anti-inflammatory effect of SGLT2 inhibitors often converge on the IL-1 pathway. [55][56][57][58][59] In this respect, SGLT2 inhibitors could represent the first class of hypoglycaemic drugs that "uncouple" feeding from the associated pro-inflammatory response. Indeed, empagliflozin reduced M1-polarized macrophage (pro-inflammatory) accumulation and induced the anti-inflammatory M2 phenotype within adipose tissue and liver in a mouse model of diet-induced obesity, which showed lower plasma cytokine levels and attenuated obesity-related chronic inflammation.…”

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes

“…Luseogliflozin also has clinical benefits for T2DM patients with nonalcoholic fatty liver disease (Shibuya et al, ). It could also offer potential benefit for the cardiovascular system through reducing epicardial fat accumulation, exerting an antiatherosclerotic effect and lowering blood pressure (Bouchi et al, ; Kosiborod et al, ; Nakatsu et al, ; Takenaka, Ohno, & Suzuki, ).…”