Canagliflozin attenuates isoprenaline-induced cardiac oxidative stress by stimulating multiple antioxidant and anti-inflammatory signaling pathways

Abstract

The antidiabetic drug canagliflozin is reported to possess several cardioprotective effects. However, no studies have investigated protective effects of canagliflozin in isoprenaline (ISO)-induced cardiac oxidative damage-a model mimicking sympathetic nervous system (SNS) overstimulation-evoked cardiac injuries in humans. Therefore, we investigated protective effects of canagliflozin in ISOinduced cardiac oxidative stress, and their underlying molecular mechanisms in Long-Evans rat heart and in HL-1 cardiomyocyte cell line. Our data showed that ISO administration inflicts pro-oxidative changes in heart by stimulating production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In contrast, canagliflozin treatment in ISO rats not only preserves endogenous antioxidants but also reduces cardiac oxidative stress markers, fibrosis and apoptosis. Our Western blotting and messenger RNA expression data demonstrated that canagliflozin augments antioxidant and anti-inflammatory signaling involving AMP-activated protein kinase (AMPK), Akt, endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In addition, canagliflozin treatment attenuates pro-oxidative, pro-inflammatory and proapoptotic signaling mediated by inducible nitric oxide synthase (iNOS), transforming growth factor beta (TGF-β), NADPH oxidase isoform 4 (Nox4), caspase-3 and Bax. Consistently, canagliflozin treatment improves heart function marker in ISO-treated rats. In summary, we demonstrated that canagliflozin produces cardioprotective actions by promoting multiple antioxidant and antiinflammatory signaling. Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, belongs to a new class of antidiabetic drugs prescribed for the management of type 2 diabetes mellitus (T2DM) 1. Accumulating evidence suggests that canagliflozin exhibits a range of cardiovascular effects that are independent of glucose lowering. According to recent preclinical and clinical data, canagliflozin treatment significantly reduced risk of cardiovascular death, myocardial infarction (MI), stroke and hospitalization due to heart failure in both diabetic and non-diabetic subjects 2-5. Proposed mechanisms for cardiovascular benefits of canagliflozin include improvement of cardiac metabolism and diastolic function, reduction of vascular stiffness, and an overall reduction of blood pressure 5-9. A growing body of evidence suggests that canagliflozin possess antioxidant and anti-inflammatory actions in various cellbased and animal models 10-14. Canagliflozin was shown to reduce vascular inflammation and atherosclerosis by

Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

“…These results indicated that CAN affects glucose and lipid metabolism and then improves heart dysfunctions likely by targeting kidney SGLT2 and promoting urine glucose excretion. However, in another non-diabetic model, CAN did not affect glucose and lipid metabolism but still improved heart functions (Hasan et al, 2020). Our present result in vitro also indicated that CAN exerts a direct protective effect in cardiomyocytes independently of glucose and lipid metabolism.…”

Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels

“…SGLT2 inhibitors including empagliflozin have been shown to have a wide range of effects in the cardiovascular system and beyond [ 5 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ] Although they are primarily recommended for decreasing renal glucose reabsorption by selectively blocking SGLT2 [ 55 ], this class of drugs appears to have many other molecular targets that result in a range of glucose independent beneficial effects or ‘pleiotropic’ effects. Since SGTL2 has the highest concentration in the renal proximal tubule, the vasodilatory action of empagliflozin in mesenteric artery may be another example of a pleiotropic effect of SGLT2 inhibitors.…”

“…Considering the interval-ratio data with normal distribution, we performed unpaired Student’s t -tests (two-tailed) to test hypotheses. A p value of <0.05 was considered statistically significant [ 28 , 29 , 39 ].…”

“…This raises the possibility that empagliflozin may also relax and reduce the resistance of systemic vessels such as small mesenteric arteries. Moreover, empagliflozin and other SGTL2 inhibitors were reported to possess significant antioxidant and anti-inflammatory actions that afford protection against nitro-oxidative stress and suppress vascular inflammation and atherosclerosis [ 5 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In this study, we investigated vasodilatory action of acute empagliflozin application in freshly isolated, resistance-size mesenteric arteries by using pressure myography and pharmacological approaches.…”

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

“…In addition, AMPK improves NO bioavailability by downregulating NOX4 expression, as demonstrated by studies using different drugs able to active AMPK [59]. For instance, Hasan et al have recently demonstrated that canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in T2DM treatment, ameliorates a cardiac oxidative microenvironment by AMPK/NOX4 signaling [60]. In the same manner, SIRT1 plays a fundamental role in eNO expression.…”