The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

Abstract

Background Myocardial fibrosis is a multistep process, which results in collagen deposition in the injured muscle. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), decreases cardiovascular events risk. Little is known on the effects of empagliflozin in non-diabetic patients early post myocardial infarction. Methods Fourteen non-diabetic rats underwent myocardial infarction induction, and treated or not (control)immediately after myocardial infarction by daily empagliflozin (30 mg/kg/day). We evaluated cardiac function at baseline, 2 and 4 weeks after myocardial infarction by echocardiography, and prior to sacrifice by Millar pressure–volume system. We performed histological and biochemical evaluation of fibrosis and humoral factors promoting fibrosis. Results Baseline ejection fractions were 69.9 ± 5.3% and 76.4 ± 5.4%, and dropped to final values of 40.1 ± 5.8% and 39.4 ± 5.4% in the control and empagliflozin groups, respectively (P < 0.001 vs. baseline, P > 0.05 between groups). Collagen deposition, measured as collagen volume fraction, was higher in both the scar and the remote cardiac areas of the control group 79.1 ± 6.2% and 4.6 ± 2.5% for control, and 53.8 ± 5.4% and 2.5 ± 1.3% for empagliflozin group, respectively (P < 0.05 for each). Remote cardiac muscle collagen, measured by hydroxyproline, was 4.1 ± 0.4 μg/μl and 3.6 ± 0.2 μg/μl (P = 0.07). TGF-β1 and Smad3 expression decreased by empagliflozin—18.73 ± 16.32%, 9.16 ± 5.69% and 16.32 ± 5.4%, 7.00 ± 5.28% in the control and empagliflozin groups, respectively (P < 0.05). Conclusion/interpretation Empagliflozin administered early after myocardial infarction reduce myocardial fibrosis and inhibit the TGF-β1/Smad3 fibrotic pathway, probably prior to exerting any hemodynamic or physiological effect.

Effect of Low-Frequency Non-Invasive Therapeutic Ultrasound on Attenuation of Cardiac Fibrosis Early After Myocardial Infarction in Rats

“…Kang et al showed in an in vitro set-up, that collagen deposition reduction may involve the inhibition of the TGF-β1/smad3 pathway [9]. Lately, we have shown in an in vivo set-up that empagli ozin attenuates TGF-β1/smad3 expression, and concomitantly, affected collagen deposition in non-diabetic rats post MI [10], thus, establishing further the involvement of this pathway in brosis.…”

“…Smad3 is an essential component in the signaling pathway of TGF-β, which rests downstream to the TGF-β receptors [32]. Lately, we showed that empagli ozin, a sodium/glucose transporter 2 inhibitor, also attenuate the TGF-β1/smad3 pathway and prevent post-MI brosis and preserves cardiac structure [10]. Here, we show that spironolactone, but not TUS, affects the downstream components of this pro-brotic pathway, smad3 [32].…”

“…Rats underwent MI procedure, as previously described by Daud et al [10]. Brie y, under deep anesthesia with a mixture of 87mg/kg ketamine and 13 mg/kg xylazine rats were intubated and ventilated at a rate of 80-90 breaths x min −1 and 1 to 2 ml x (100 gr) −1 tidal volume.…”

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

“…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.…”

Anti-Arrhythmic Effects of Sodium-Glucose Co-Transporter 2 Inhibitors

“…SGLT2i can improve cardiac structural remodeling (Chowdhury et al, 2020;Madonna et al, 2020;Sun et al, 2020;Shentu et al, 2021). EMPA was reported to affect the oxidative stress and fibrosis by inhibiting the TGF-β/Smad signaling pathway Daud et al, 2021) and activate the Nrf2/ARE signaling pathway in cardiomyocytes in the T2MD mouse model . DAPA also inhibits fibroblast activation and myocardial fibrosis (Shih et al, 2021;Tian et al, 2021) by inhibiting the TGF-β/Smad signaling pathway (Tian et al, 2021) in T2MD rats.…”