This preprint is under consideration at Cardiovascular Diabetology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Original investigation
Dajun Chai
Cardiovascular Department, The First Affiliated Hospital of Fujian Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9477-9956
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background:
Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms.
Methods:
Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II with or without the indicated concentration of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes.
Results:
DAPA treatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA treatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling.
Conclusion:
DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a glucose-independent manner. DAPA may serve as a novel therapy for pathological cardiac remodeling.
Keywords
Sodium-glucose cotransporter 2 inhibitors, Dapagliflozin, Angiotensin II, Cardiac fibrotic remodeling, TGFβ1/ Smad signaling
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CURRENT STATUS: Under Revision
Version 1
Posted 11 Mar, 2021
No community comments so far
Review #3 received
Received 29 Mar, 2021
Editorial decision: Major Revision
On 29 Mar, 2021
Review #1 received
Received 16 Mar, 2021
Review #2 received
Received 09 Mar, 2021
Reviewer #3 agreed
On 05 Mar, 2021
Reviewer #2 agreed
On 04 Mar, 2021
Reviewers invited
Invitations sent on 04 Mar, 2021
Review #? received
Received 04 Mar, 2021
Editor assigned
On 04 Mar, 2021
Reviewer #1 agreed
On 04 Mar, 2021
Submission checks complete
On 04 Mar, 2021
Editor invited
On 04 Mar, 2021
First submitted
On 01 Mar, 2021
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Subject Areas
Cardiac & Cardiovascular Systems
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This preprint is under consideration at Cardiovascular Diabetology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Original investigation
Dajun Chai
Cardiovascular Department, The First Affiliated Hospital of Fujian Medical University
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9477-9956
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 11 Mar, 2021
No community comments so far
Review #3 received
Received 29 Mar, 2021
Editorial decision: Major Revision
On 29 Mar, 2021
Review #1 received
Received 16 Mar, 2021
Review #2 received
Received 09 Mar, 2021
Reviewer #3 agreed
On 05 Mar, 2021
Reviewer #2 agreed
On 04 Mar, 2021
Reviewers invited
Invitations sent on 04 Mar, 2021
Review #? received
Received 04 Mar, 2021
Editor assigned
On 04 Mar, 2021
Reviewer #1 agreed
On 04 Mar, 2021
Submission checks complete
On 04 Mar, 2021
Editor invited
On 04 Mar, 2021
First submitted
On 01 Mar, 2021
Subject Areas
Cardiac & Cardiovascular Systems
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background:
Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms.
Methods:
Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II with or without the indicated concentration of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes.
Results:
DAPA treatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA treatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling.
Conclusion:
DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a glucose-independent manner. DAPA may serve as a novel therapy for pathological cardiac remodeling.
Figure 1
Figure 2
Figure 3
Figure 4
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