Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

Abstract

Background The novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms. Methods and results Migration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca2+ fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca2+ leakage, Ca2+ entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na+-H+ exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca2+ leakage, Ca2+ entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. Conclusions By inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca2+ release, extracellular Ca2+ entry and the profibrotic activities of atrial fibroblasts.

Myocardial sodium–glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO‐AS study

“…38 In line with these findings, empagliflozin has been shown to inhibit cardiac fibrogenesis by inhibiting the NHE and modulating Ca ++ homeostasis. 38 Remarkably, all the above-mentioned pathways interact with each other, creating a harmful vicious cycle (Figure 5). Over time, this structural-metabolic imbalance increases the risk of reduced LVEF and the development of HF.…”

“…Of particular interest is the role of NHE, which, when hyper‐expressed, has been associated with increased expression of phosphorylated phospholipase and inositol triphosphate. This leads to enhanced release of Ca ++ from the endoplasmic reticulum, increased entry of extracellular Ca ++ , and activation of profibrotic activities in atrial fibroblasts 38 . In line with these findings, empagliflozin has been shown to inhibit cardiac fibrogenesis by inhibiting the NHE and modulating Ca ++ homeostasis 38 …”

“…This leads to enhanced release of Ca ++ from the endoplasmic reticulum, increased entry of extracellular Ca ++ , and activation of profibrotic activities in atrial fibroblasts 38 . In line with these findings, empagliflozin has been shown to inhibit cardiac fibrogenesis by inhibiting the NHE and modulating Ca ++ homeostasis 38 …”

Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials

“…This may be related to the mode of action of SGLT2i, which may indirectly reduce fibrosis as a consequence of an improvement in cardiac and renal (and possibly hepatic) metabolism, and not via a direct anti-fibrotic effect. 42 While experimental studies in rats suggest that SGLT2i reduce myocardial fibrosis, 25,43,44 such an effect is yet to be demonstrated in humans, despite improvements in cardiac structure and function assessed by cardiac magnetic resonance with SGLT2i. [45][46][47] Our study suggests that empagliflozin may reduce the synthesis of collagen type I and III, a reduction that is not organ-specific that is, it may reflect reduced collagen synthesis in the heart, vessels, kidneys, liver, and even bone or skin.…”

Advancing the fight against fibrosis in patients with heart failure: The contribution of sodium–glucose cotransporter 2 inhibition

“…inhibition of sodium–hydrogen exchanger‐1) and reduce MIF. Although there is in vitro experimental evidence in human cardiac fibroblasts that supports this hypothesis, 17 more research will be required.…”