Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

Abstract

Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy.

Keywords: Diabetic cardiomyopathy; Mechanisms; Sodium-glucose cotransporter 2 inhibitor.

Fig. 1

SGLT2 inhibitors improve mitochondrial function. SGLT2 inhibitors activate the AMPK/PGC-1α signalling pathway, thereby increasing PGC-1α-regulated NRF-1 expression, which increases mtTFA expression and further promotes mitochondrial biogenesis. PGC-1α can also inhibit Drp1-induced mitochondrial fission and activate key enzymes, including cytochrome c oxidase, in mitochondria, which can increase the efficiency of electron transfer. Activation of AMPK, on the other hand, leads to the recovery of abnormal MFN1, MFN2, and OPA1, reducing mitochondrial fission

Fig. 2

SGLT2i can improve vasodilatory inflammation by decreasing uric acid levels. In proximal renal tubules, SGLT2i acts on SGLT2, decreasing the reabsorption of Na ions and glucose and increasing glucose concentrations in the lumen, which is exchanged with uric acid by GLUT9 isoform 2. This leads to increased uric acid exclusion. In the collecting duct, high levels of glucose inhibit this exchange and reduce the absorption of uric acid, thereby draining it. Lowering the concentration of uric acid in the blood helps reduce inflammation in the blood vessels

Fig. 3

SGLT2i can improve vasodilatory functions through COX-2. In endothelial cells, SGLT2i inhibit the production of ROS-induced PGH2 by inhibiting COX-2 and reduce the production of PGE2 and TXA2 downstream of PGH2. In vascular smooth muscle, although PGE2 activates EP4 receptors to dilate blood vessels, TAX2 activates TP receptors to cause vasoconstriction. In addition, downstream EP4 can cascade into ERK1/2/NOX4 to produce ROS, which contributes to vasoconstriction and the activation of COX-2. In vascular smooth muscle, COX-2 activates and catalyses AA to produce PGH2, which constricts blood vessels

Fig. 4

Histological data on the improvements in myocardial fibrosis by empagliflozin [102]. SGLT2 inhibitor empagliflozin played an important role in improving myocardial fibrosis of diabetic mice (genetic type 2 diabetes model) through reducing the expression of relevant signaling molecules and collagen. Compared with diabetic mice without empagliflozin treatment, it significantly reduced the expression of TGF-β1, p-Smad2, p-Smad3, collagen I, and collagen III. This kind of improvement represented the reduction in matrix accumulation and the betterment of ventricular compliance. Copyright 2019, Cardiovasc Diabetol.

Fig. 5

The SGLT2 inhibitor improves pyroptosis and reduces cardiac fibrosis. Activation of AMPK by the SGLT2 inhibitor decreases the expression of downstream NLRP3, Caspase-1 and ACS. Therefore, the upregulation of the NLRP3 inflammasome complex is inhibited, which reduces the transformation of procaspase-1 to active caspase-1 and the transformation of proIL-1β and proIL-18 to IL-1β and IL-18, respectively, to inhibit pyroptosis. As a result of the decrease in IL-1β, the activation of IL-1βR is correspondingly decreased, and the expression of TGF-β in the downstream signalling pathway is reduced, resulting in a relative reduction in fibrosis

Fig. 6

The SGLT2 inhibitor improves ER stress. SGLT2 inhibitor treatment inhibits the loss of GRP78 from transducers by activating Sirt1, thus inhibiting the development of ER stress. The downstream signalling pathways of PERK, ATF6 and IRE1α can induce the transcription of CHOP. CHOP upregulates the expression of the pseudokinase tribbles homologue 3 gene and weakens the inhibitory effect of AKT on the expression of caspase-9 and caspase-3. On the other hand, CHOP promotes the expression of Bax and Bak and inhibits the expression of Bcl-2, Bcl-XL and MCL-1. IRE1α also promotes apoptosis by sequentially activating ASK1 and JNK