Dapagliflozin prevents ERK activation and SGLT2-dependent endoglin upregulation in a mechanically provoked cardiac injury model
© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society..
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI) by an unknown mechanism. Upregulation of Na+/H+ exchanger 1 (NHE1), SGLT1, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na+/Ca2+ homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na+/Ca2+ homeostasis via ERK and eNOS signaling. AMI (+) and AMI (-) serum levels were estimated using ELISA assays of TGFβ-1 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 levels was performed for 5% (mild), and 25% elongation for 24 h. AMI (+) serum showed increased TGFβ1 and CD105 compared to AMI (-) patients. In consistent, troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were upregulated after 25% of 24 h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Physiological reports - 12(2024), 7 vom: 04. Apr., Seite e15990 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yeh, Tung-Chen [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
1ULL0QJ8UC |
|---|
| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 08.04.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.14814/phy2.15990 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370649702 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370649702 | ||
| 003 | DE-627 | ||
| 005 | 20240408233018.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240405s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.14814/phy2.15990 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1369.xml |
| 035 | |a (DE-627)NLM370649702 | ||
| 035 | |a (NLM)38575554 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yeh, Tung-Chen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dapagliflozin prevents ERK activation and SGLT2-dependent endoglin upregulation in a mechanically provoked cardiac injury model |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.04.2024 | ||
| 500 | |a Date Revised 08.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. | ||
| 520 | |a Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI) by an unknown mechanism. Upregulation of Na+/H+ exchanger 1 (NHE1), SGLT1, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na+/Ca2+ homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na+/Ca2+ homeostasis via ERK and eNOS signaling. AMI (+) and AMI (-) serum levels were estimated using ELISA assays of TGFβ-1 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 levels was performed for 5% (mild), and 25% elongation for 24 h. AMI (+) serum showed increased TGFβ1 and CD105 compared to AMI (-) patients. In consistent, troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were upregulated after 25% of 24 h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a SGLT2 | |
| 650 | 4 | |a cardiac overloading | |
| 650 | 4 | |a cardiomyocytes | |
| 650 | 4 | |a cyclic stretch | |
| 650 | 7 | |a dapagliflozin |2 NLM | |
| 650 | 7 | |a 1ULL0QJ8UC |2 NLM | |
| 650 | 7 | |a Endoglin |2 NLM | |
| 650 | 7 | |a Sodium-Glucose Transporter 2 |2 NLM | |
| 650 | 7 | |a Troponin I |2 NLM | |
| 650 | 7 | |a Benzhydryl Compounds |2 NLM | |
| 650 | 7 | |a Glucosides |2 NLM | |
| 700 | 1 | |a Wu, Yi-Chung |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Tzyy Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Gwo-Ching |e verfasserin |4 aut | |
| 700 | 1 | |a Tseng, Ching-Jiunn |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Pei-Wen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Physiological reports |d 2013 |g 12(2024), 7 vom: 04. Apr., Seite e15990 |w (DE-627)NLM228197236 |x 2051-817X |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2024 |g number:7 |g day:04 |g month:04 |g pages:e15990 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.14814/phy2.15990 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2024 |e 7 |b 04 |c 04 |h e15990 | ||