Empagliflozin maintains capillarization and improves cardiac function in a murine model of left ventricular pressure overload

Abstract

Patients with type 2 diabetes treated with Sodium glucose transporter 2 (SGLT2) inhibitors show reduced mortality and hospitalization for heart failure (HF). SGLT2 inhibitors are considered to activate multiple cardioprotective pathways; however, underlying mechanisms are not fully described. This study aimed to elucidate the underlying mechanisms of the beneficial effects of SGLT2 inhibitors on the failing heart. We generated a left ventricular (LV) pressure overload model in C57BL/6NCrSlc mice by transverse aortic constriction (TAC) and examined the effects of empagliflozin (EMPA) in this model. We conducted metabolome and transcriptome analyses and histological and physiological examinations. EMPA administration ameliorated pressure overload-induced systolic dysfunction. Metabolomic studies showed that EMPA increased citrulline levels in cardiac tissue and reduced levels of arginine, indicating enhanced metabolism from arginine to citrulline and nitric oxide (NO). Transcriptome suggested possible involvement of the insulin/AKT pathway that could activate NO production through phosphorylation of endothelial NO synthase (eNOS). Histological examination of the mice showed capillary rarefaction and endothelial apoptosis after TAC, both of which were significantly improved by EMPA treatment. This improvement was associated with enhanced expression phospho-eNOS and NO production in cardiac endothelial cells. NOS inhibition attenuated these cardioprotective effects of EMPA. The in vitro studies showed that catecholamine-induced endothelial apoptosis was inhibited by NO, arginine, or AKT activator. EMPA activates the AKT/eNOS/NO pathway, which helps to suppress endothelial apoptosis, maintain capillarization and improve systolic dysfunction during LV pressure overload.

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

“…The endothelial protective effects of empagliflozin have been described in several in-depth studies. In transverse aortic constriction-induced heart failure, empagliflozin was reported to suppress endothelial apoptosis and maintain capillarization through the Akt/eNOS/nitric oxide pathway, thus increasing heart performance [ 18 , 50 ]. Similarly, empagliflozin was found to inhibit leukocyte-endothelium interactions during diabetes by repressing inflammatory cytokine production [ 51 ].…”

“…It is well documented that the intracellular effectors of empagliflozin include extracellular signal-regulated kinase 1/2 [ 65 ], phosphoinositide 3-kinase/Akt [ 18 ], transforming growth factor β1 [ 66 ], nuclear factor κB [ 67 ], Janus kinase 2 [ 67 ], Sirtuin 1 [ 68 ], hypoxia inducible factor 1α [ 69 ], protein kinase G Iα [ 70 ], heme oxygenase 1 [ 71 ], peroxisome proliferator-activated receptor gamma coactivator 1α [ 72 ] and AMPKα1 [ 20 ]. Among them, AMPK has been identified as an indispensable inducer of mitophagy.…”

“…Functional analyses indicated that empagliflozin administration improved the ratio of adenosine monophosphate (AMP) to adenosine triphosphate (ATP) in cardiomyocytes, thus accelerating glucose metabolism and increasing cell viability [ 17 ]. Animal studies and molecular experiments have illustrated that empagliflozin protects not only cardiomyocytes, but also endothelial cells; for instance, empagliflozin increased phosphorylated endothelial nitric oxide synthase (p-eNOS) expression and nitric oxide production in cardiac endothelial cells in a murine model of heart failure [ 18 ]. Empagliflozin also attenuated oxidative stress-induced endothelial barrier dysfunction through an undefined mechanism [ 19 ].…”

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

“…Although the first interest in SGLT2i was their glucose-lowering capacity, lately there have been described pleiotropic effects of SGLT2i in a wide range of targets throughout the body ( Figure 2 ). Using different experimental approaches and in different scenarios, SGLT2i have been shown to participate in the regulation of osmotic natriuresis and diuresis [ 103 , 104 ], hypertension [ 105 ], glucagon [ 106 , 107 ] and energy metabolism [ 108 , 109 , 110 , 111 , 112 ], mitochondrial function and biogenesis [ 113 , 114 , 115 , 116 , 117 , 118 ], autophagy [ 112 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ], oxidative stress [ 46 , 123 , 126 , 127 , 128 , 129 ], fibrosis [ 46 , 130 , 131 , 132 , 133 ], apoptosis [ 122 , 128 , 134 , 135 , 136 , 137 , 138 , 139 ], endoplasmic reticulum stress [ 124 , 139 , 140 , 141 , 142 , 143 ], or inflammation [ 120 ,…”

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

“…Empagliflozin improved renal ischemia/reperfusion injury in non-diabetic rats by promoting mitochondrial biogenesis and inhibiting oxidative stress and apoptosis ( 66 ). In the murine model of left ventricular pressure overload, empagliflozin aids the suppression of endothelial apoptosis, the maintenance of capillarization, and the improvement of cardiac systolic dysfunction ( 67 ). MAPK3/MAPK1, also known as extracellular signal-regulated kinase 1/2 (ERK1/2), is a member of the MAPK protein family ( 68 ).…”