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Carvedilol Diminishes Cardiac Remodeling Induced by High-Fructose/High-Fat Diet in Mice via Enhancing Cardiac
Wael S Ibrahim1,2, Islam A A E-H Ibrahim1, Mona F Mahmoud1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Background:
Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac β-arrestin2 signaling, and the protective effects of carvedilol as a β-arrestin-biased agonist.
Methods And Results:
Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, β-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, β-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, β-arrestin2, PIP2, and pS473 Akt.
Conclusion:
Carvedilol enhances cardiac β-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.
Insights
This study shows that a high-fructose/high-fat diet induces insulin resistance and cardiac remodeling in mice. Carvedilol treatment improved cardiac function by enhancing beta-arrestin2 signaling.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Pharmacology
Background:
- Insulin resistance (IR) is a significant risk factor for cardiovascular complications.
- Dietary models are crucial for studying IR-induced cardiac changes.
- Beta-arrestin2 signaling plays a role in cardiac pathophysiology.
Purpose of the Study:
- To investigate the impact of a dietary model of IR on cardiac remodeling and beta-arrestin2 signaling in mice.
- To evaluate the protective effects of carvedilol, a beta-arrestin-biased agonist, in this model.
Main Methods:
- Mice were fed a high-fructose/high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance.
- Carvedilol was administered for the last 4 weeks of the study.
- Cardiac remodeling, beta-arrestin2 signaling, and metabolic parameters were assessed.
Main Results:
- HFrHFD induced insulin resistance, cardiac fibrosis, and myofibril degeneration, with reduced cardiotrophin-1, beta-arrestin2, PIP2, and pS473 Akt.
- Carvedilol treatment mitigated these effects, reducing cardiac remodeling markers and improving metabolic parameters.
- Carvedilol significantly increased cardiac cardiotrophin-1, beta-arrestin2, PIP2, and pS473 Akt levels.
Conclusions:
- Carvedilol demonstrates protective effects against diet-induced cardiac remodeling in mice with insulin resistance.
- The drug enhances cardiac beta-arrestin2 signaling, suggesting a therapeutic mechanism.
- Targeting beta-arrestin2 signaling may be a viable strategy for managing cardiovascular complications of insulin resistance.
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