Dapagliflozin Mitigates Doxorubicin-Caused Myocardium Damage by Regulating AKT-Mediated Oxidative Stress, Cardiac Remodeling, and Inflammation

Abstract

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.

Effect of renal denervation on cardiac remodelling and function in rats with chronic intermittent hypoxia

“…Activation of Nrf2 protected the heart against myocardial dysfunction and fibrosis, while knockdown of Nrf2 promoted cardiac fibrosis 26 . HO‐1, SOD and NQO1, as the downstream of Nrf2, are also beneficial to cardiovascular systems by exerting anti‐inflammatory and antioxidant effects 27,28 . In the present study, CIH lowered the expression of myocardial Nrf2 and HO‐1, which may contribute to the cardiac maladaptive response to CIH, including cardiac remodelling, fibrosis and dysfunction.…”

“…26 HO-1, SOD and NQO1, as the downstream of Nrf2, are also beneficial to cardiovascular systems by exerting anti-inflammatory and antioxidant effects. 27,28 In the present study, CIH lowered the expression of myocardial Nrf2 and HO-1, which may contribute to the cardiac maladaptive response to CIH, including cardiac remodelling, fibrosis and dysfunction. In this case, RDN exerts its protective effects by activating the Nrf2/HO-1 pathway, reflected by attenuation of cardiac fibrosis, increased SOD and NQO1 level and decreased inflammatory response after RDN.…”

Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity

“…These findings were in line with previous studies. [41][42][43][44][45][46] These protective properties of DAP were detected in other forms of cardiac injuries including diabetic cardiomyopathy, doxorubicin cardiotoxicity, ischemia reperfusion models, myocardial infarction and heart failure. [51][52][53] These effects were based upon its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties and regulation of RAAS with preservation of the myocardium.…”

“…This is in accordance with previous studies of DAP in other cardiotoxic models. [43][44][45][46][47] In addition, VEGF is not only expressed in vascular endothelium, but also it was reported to be expressed in macrophages around the infarcted tissue and it has essential roles in myocardial repair. [40][41][42][48][49][50] SGLT2 is a new class of oral anti-diabetic agents used mainly for lowering blood glucose levels in type 2 diabetic patients.…”

Guideline-directed medical therapy in chemotherapy-induced cardiotoxicity and heart failure: current perspectives and practices

“…Additionally, SGLT2i have emerged as a potential therapeutic avenue for CIC prevention and treatment [56] . These drugs exhibit a range of pleiotropic effects, such as improving endothelial function, reducing oxidative stress, and modulating cardiac metabolism, which further contribute to their cardioprotective properties [57][58] . These properties make SGLT2i a compelling candidate for augmenting GDMT in CIC.…”