Dapagliflozin Ameliorates STZ-Induced Cardiac Hypertrophy in Type 2 Diabetic Rats by Inhibiting the Calpain-1 Expression and Nuclear Transfer of NF-κB

Abstract

Objective. To investigate the effect of dapagliflozin (DAPA) on cardiac hypertrophy induced by type 2 diabetes mellitus (T2DM) and its mechanism. Methods. SD rats with T2DM were divided into a T2DM group ( n = 6 ) and DAPA group ( n = 6 ). They were, respectively, fed with the same amount of normal saline and 1 mg/kg DAPA. The control group ( n = 6 ) was also fed with normal saline. The hearts were tested by the application of echocardiography and hemodynamics. Subsequently, fasting blood glucose (FBG), serum total cholesterol (TC), and triglyceride (TG) as well as interleukin- (IL-) 10, IL-6, and tumor necrosis factor (TNF)-α in serum were tested. H&E and Masson staining was performed to observe the degree of cardiac tissue lesions, and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), calpain-1, p-IκBα, and p65 in myocardial tissue was tested by qRT-PCR and Western blot. Results. Compared with the control group, rats in the T2DM group exhibited significant diabetic symptoms: FBG was significantly elevated, and the levels of TC, TG, IL-6, and TNF-α were significantly increased, while the levels of IL-10 and the calpain activity were evidently decreased. However, DAPA treatment could improve the above changes. At the same time, the damage and fibrosis of the heart tissue in the DAPA group were markedly improved. Additionally, the mRNA expression of ANP and BNP in myocardial tissue of the DAPA group was markedly increased. And DAPA could inhibit the expression of p-IκBα/IκBα in the cytoplasm and p65 in the nucleus as well as the expression of calpain-1 in myocardial tissue. Conclusion. DAPA treatment ameliorates the cardiac hypertrophy caused by T2DM by decreasing body blood glucose, while reducing the expression of calpain-1 in cardiomyocytes and inhibiting the nuclear translocation of NF-κB.

An integrated RNA sequencing and network pharmacology approach reveals the molecular mechanism of dapagliflozin in the treatment of diabetic nephropathy

“…Complement C3 was proved to be negatively related to the glomerular filtration rate in patients with DN and could be immune-related biomarkers of DN ( 53 ). It has been reported that dapagliflozin can attenuate complement over-activation and upregulate the anti-inflammatory cytokine IL-10 in diabetic mice ( 30 , 54 ), which consisted with our results again. Recent studies showed that CASP3 was upregulated in diabetic rats and diabetic human kidney tubuli ( 55 , 56 ).…”

Dapagliflozin Improves Diabetic Cardiomyopathy by Modulating the Akt/mTOR Signaling Pathway

“…In addition, it can restore the oxidant/antioxidant balance and attenuates inflammation and downregulates the levels of apoptosis key elements in myocardial tissue [ 24 ]. Dapagliflozin obviously improves myocardial hypertrophy caused by T2DM by reducing blood glucose and the expression of calpain-1 in cardiomyocytes [ 25 ]. Herein, our experiment was to explore whether dapagliflozin recovered autophagy through the Akt/mTOR signaling pathway and to observe the expression and distribution of Cx43 in ventricular myocytes upon treatment.…”

The Effects of Low-Dose Empagliflozin on Cardiac Function and Β-Adrenoceptor Responses in a Rat Model of Streptozotocin-Induced Diabetes

“…SGLT2 inhibitors are approved for the treatment of T2DM and at least some (dapagliflozin and EMPA) irrespective of diabetic status also for the treatment of heart failure. According, their effects on the heart have been studied in various rodent models of T2DM [17][18][19][20][21][22][24][25][26][27][28]. Although SGLT2 inhibitors are not used for the treatment of T1DM, some studies have explored their cardiac effects in STZ-based rat and mouse models thereof [29][30][31][32], where they also exhibited beneficial effects.…”

“…The effects of SGLT2 inhibitors have been explored in various rodent models of diabetes-associated cardiomyopathy. These have used T2DM models including ob/ob mice [17,18], db/db mice with or without additional angiotensin II infusion [19,20], rats [21][22][23] and mice [24] treated with a combination of a high-fat diet (HFD) and injection of streptozotocin (STZ), Zucker diabetic fatty rats [25], seipin knock-out mice [26], a cross-breed of mRen27 and Tet29 rats [27], and Dahl salt-sensitive rats on a high-sodium diet [28]. They have used various SGLT2 inhibitors including canagliflozin, dapagliflozin and EMPA.…”

“…Our experiments have initiated EMPA treatment 13-16 weeks after STZ injection, i.e., at a time point when diabetic cardiomyopathy can be expected to have fully developed. This is later than most other studies in the field, which started SGLT2 inhibitor treatment in most cases ≤1 week after STZ injection [21,23,24,29,[31][32][33][34], and only rarely at later time points such as 2 weeks [30] or 8 weeks after STZ injection [22]. We consider our approach to have higher translational validity as the diagnosis of T2DM typically is made only at a time considerably after onset of the disease.…”