Canagliflozin Prevents Lipid Accumulation, Mitochondrial Dysfunction, and Gut Microbiota Dysbiosis in Mice With Diabetic Cardiovascular Disease

Abstract

Type 2 diabetes mellitus (T2DM) is associated with cardiovascular disease (CVD) and sodium glucose cotransporter 2 inhibitors, as oral medications for T2DM treatment have shown the potential to improve vascular dysfunction. The aim of this study was to evaluate the ability of canagliflozin (Cana) to relieve CVD in T2DM mice and its possible action mechanism. Mice with diabetic CVD was conducted by a high-fat diet for 24 weeks, followed by oral gavaging with metformin (200 mg/kg/day) or Cana (50 mg/kg/day) for 6 weeks. The result demonstrated that Cana reduced serum lipid accumulation, and decreased the arteriosclerosis index and atherogenic index of plasma. In addition, Cana treatment reduced the circulating markers of inflammation. More importantly, Cana improved cardiac mitochondrial homeostasis and relieved oxidative stress. Moreover, Cana treatment alleviated the myocardial injury with decreasing levels of serous soluble cluster of differentiation 40 ligand and cardiac troponin I. Thus, cardiovascular abnormality was relieved by suppressing fibrosis and basement membrane thickening, while elevating the cluster of differentiation 31 expression level. Importantly, Cana increased the ratio of gut bacteria Firmicutes/Bacteroidetes and the relative abundance of Alistipes, Olsenella, and Alloprevotella, while it decreased the abundance of Mucispirillum, Helicobacter, and Proteobacteria at various taxonomic levels in mice with diabetic CVD. In short, Cana treatment altered the colonic microbiota composition close to the normal level, which was related with blood lipid, inflammation, and oxidative stress, and might play a vital role in CVD. In general, the improvements in the gut microbiota and myocardial mitochondrial homeostasis may represent the mechanism of Cana on CVD treatment.

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

“…Canagliflozin (Cana), a hypoglycemic drug of sodium-glucose cotransporter 2 inhibitor (SGLT2i), has shown promising anticardiovascular effect in multicenter clinical randomized doubleblind studies, which can reduce the risk of cardiovascular death or hospitalization for heart failure in diabetic patients and nondiabetic patients (10,11). Meanwhile, Cana have shown the ability to attenuate oxidative stress and improve myocardial function by suppressing apoptosis, promoting antioxidant and antiinflammatory pathways (11,12). At present, the protective effects of Cana on the heart have been gradually revealed in various myocardial injuries, such as autoimmune myocarditis (13), myocardial lipotoxicity (12) and even isoprenaline-induced cardiotoxicity (14).…”

“…Meanwhile, Cana have shown the ability to attenuate oxidative stress and improve myocardial function by suppressing apoptosis, promoting antioxidant and antiinflammatory pathways (11,12). At present, the protective effects of Cana on the heart have been gradually revealed in various myocardial injuries, such as autoimmune myocarditis (13), myocardial lipotoxicity (12) and even isoprenaline-induced cardiotoxicity (14). In addition, a recent study reported that Cana may exert its cardiovascular benefits partly via its mitigation of ferroptosis (15), which is similar to the effect of empagliflozin ( 16), another SGLT2i.…”

The Effects of Cardioprotective Antidiabetic Therapy on Microbiota in Patients with Type 2 Diabetes Mellitus—A Systematic Review

“…Dapagliflozin, empagliflozin, and canagliflozin revealed favorable effects on microbiota with tight interactions with T2DM, metabolic syndrome, and CVD in studies on mice [ 55 , 56 , 57 , 58 ]. Researchers used different rat categories, from diet-induced mice to subjects with nephropathy, and this heterogeneity overburdened the challenge of analyzing the impact of SGLT-2i on the microbiota.…”

“…Standardization is another important aspect that has to be considered, as the participants’ characteristics can also induce different baseline microbiota distributions. The differences between interspecies in terms of gut microbiota should not be overlooked, acknowledging the fact that the data from the studies on mice microbiota cannot be extrapolated to human subjects [ 56 , 57 , 58 , 59 ]. We have to consider the interracial differences in terms of the gut microbial architecture, because patients from different geographical areas may have different microbial signatures, partly because of genetic factors but also due to external factors, such as cultural patterns (different diet) or various environmental factors.…”

Porphyran From Porphyra haitanensis Alleviates Obesity by Reducing Lipid Accumulation and Modulating gut Microbiota Homeostasis

“…Partial tissues were fixed in 4% paraformaldehyde solution immediately. After dehydration and embedding, tissues were cut into 4-μm-thick sections and analyzed by H&E or Oil Red O ( Wang et al, 2021 ; Wang et al, 2022 ). Quantity was analyzed using ImageJ software.…”