IDDF2021-ABS-0198 Canagliflozin alleviates diabetic cardiovascular disease via lipid lowering, mitochondrial homeostasis, and gut microbiota regulation

Background

T2DM is associated with CVD. SGLT2i represent the most effective class of oral medications for the treatment of T2DM, and have been shown to improve generalized vascular dysfunction.

Methods

T2DM was induced by HFD to male C57BL/6J mice for 24 weeks. After that, HFD-fed mice were treated with Cana (50 mg/kg/d) by oral gavage for 6 weeks. Myocardial mitochondrial morphology and cardiovascular abnormalities were assessed by TEM, immunofluorescence staining and Masson's staining; lipids profile and oxidative stress state were assessed by corresponding biochemical assay kits and immunohistochemical staining; the myocardial injury was characterized by H&E staining, TUNEL, and ELISA assays; colonic gut microbiota was assessed by 16S rDNA sequencing.

Results

Cana reduced the lipid (such as TG, TC, and LDL-C) accumulation in serum, thus decreased atherogenic index of plasma and arteriosclerosis index values. More importantly, Cana decreased the thickness of the vascular basement membrane, improved cardiac mitochondrial homeostasis, and relieved oxidative stress (e.g. regulation of ROS, SOD, GSH, and MDA levels). And, Cana reduced the circulating markers of inflammation (such as TNFα, MCP-1, and IL-6). Myocardial injury was alleviated after Cana treatment with decreasing levels of serous cTn I (from 95 pg/mL to 75 pg/mL) and sCD40L (from 120 pg/mL to 90 pg/mL). Thus, the cardiovascular abnormality was relieved by elevating the CD31 expression level and suppressing fibrosis and basement membrane thickening (from 0.6 μm to 0.2 μm) in T2DM mice. Interestingly, Cana administration increased the ratio of Firmicutes/Bacteroidetes (from 230% to 98%) and the relative abundance of Olsenella, Alistipes, and Alloprevotella, while decreasing the abundance of Helicobacter and Mucispirillum in mice with diabetic CVD.

Conclusions

Cana treatment improved CVD by decreasing the risk of atherosclerosis and reducing the thickness of the vascular basement membrane. Importantly, Cana treatment significantly elevated myocardial mitochondria homeostasis, thus ameliorated the oxidative stress and inflammatory states. Moreover, Cana subtly altered microbiota composition in T2DM mice with CVD, which contributed to the improvement of CVD. Collectively, the improvements of myocardial mitochondrial and gut microbiota homeostasis, may represent an important mechanism underlying the cardiovascular benefits of Cana treatment.