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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr-/- type 1 diabetic mice.

ABSTRACT: BACKGROUND AND AIMS:Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia. METHODS:Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout (Ldlr-/-) mice after which they were fed a high-cholesterol diet for 4 weeks. Control and diabetic mice were treated with vehicle or sodium glucose cotransporter inhibitor (SGLT2i, Phlorizin or Dapagliflozin) for the duration of the diet. RESULTS:Induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. These mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Tighter glycemic control by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver. Further examination of the liver revealed an important role for bile acid transporters (Abcg5, Abcg8) and cytochrome P450 enzymes in the clearance of hepatic cholesterol. CONCLUSIONS:These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance exclusive of Ldlr, likely via HSPG and bile acid pathways, and has an overall net positive effect on atherosclerosis.

SUBMITTER: Al-Sharea A

PROVIDER: S-EPMC7196281 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr<sup>-/-</sup> type 1 diabetic mice.

Al-Sharea Annas A Murphy Andrew J AJ Huggins L A LA Hu Y Y Goldberg Ira J IJ Nagareddy Prabhakara R PR

Atherosclerosis 20180302

<h4>Background and aims</h4>Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of ...[more]

PMID: 29518749

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Project description:BackgroundSR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested.MethodsWe tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days.ResultsPlatelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice.ConclusionsThe PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.

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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr-/- type 1 diabetic mice.

Publications

SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr<sup>-/-</sup> type 1 diabetic mice.

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