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 ISO-induced 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 pro-apoptotic 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 anti-inflammatory signaling.
Highlights
The antidiabetic drug canagliflozin is reported to possess several cardioprotective effects
We found that canagliflozin augmented heart function marker in ISO-treated rats by stimulating multiple antioxidant and anti-inflammatory signaling pathways involving AMPK, Akt, endothelial nitric oxide synthase (eNOS), Nrf[2] and heme oxygenase-1 (HO-1) to counter ISO-induced oxidative damage caused by increased inducible nitric oxide synthase (iNOS), TGF-β, Nox[4], Bax and active caspase-3
Our data showed that ISO caused significant increases in the levels of oxidative and nitrative stress markers malondialdehyde (MDA), advanced protein oxidation product (APOP), myeloperoxidase (MPO) and excessive nitric oxide (NO) in heart tissue homogenates (Fig. 2A–D)
Summary
The antidiabetic drug canagliflozin is reported to possess several cardioprotective effects. Recent studies showing in-vivo antioxidant, anti-inflammatory and cardioprotective actions of canagliflozin raise the possibility that canagliflozin may be clinically useful in cardiac oxidative damage including that caused by SNS hyperactivity. In the present study we first induced a model of chronic SNS overstimulation by administering the non-selective β-AR agonist isoprenaline (ISO) that produced profound cardiac injuries via ROS/RNS generation, inflammation and apoptosis 22,24,25, and investigated protective effects of canagliflozin and their underlying molecular mechanisms. We found that canagliflozin augmented heart function marker in ISO-treated rats by stimulating multiple antioxidant and anti-inflammatory signaling pathways involving AMPK, Akt, eNOS, Nrf[2] and HO-1 to counter ISO-induced oxidative damage caused by increased iNOS, TGF-β, Nox[4], Bax and active caspase-3. This study may open avenues for new pharmacotherapeutic indication of canagliflozin, in patients with SNS hyperactivity (Fig. 1)
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