Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis

Abstract

Sodium–glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…Here, the empagliflozin ameliorated inflammatory burden and atrial fibrosis in T2DM rats, and also improved their mitochondrial function and reduced inducible AF [154]. Empagliflozin has been reported to maintain mitochondria related cellular energetics and afford its benefits against developing adverse remodelling in post-infarction mice [23].…”

“…Numerous experimental and clinical studies suggest that oxidative stress [10] and inflammation are deleterious to cardiovascular health [11][12][13] and can increase the heart's susceptibility to arrhythmias [14][15][16][17][18][19]. While many of the cardio-protective compounds which exhibit antiarrhythmic properties are potent anti-oxidative and anti-inflammatory agents [13,[20][21][22][23]. These most likely target the primary mechanisms of pro-arrhythmia.…”

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 ,…”

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes

“…Other common pathway leading to better outcomes might be the improved mitochondrial function [ 72 , 73 ]. Improved energy production and mitochondrial biogenesis were found in experimental studies [ 74 ].…”