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Changes of Necroptosis in Irbesartan Medicated Cardioprotection in Diabetic Rats
Qingmei Xu1, Xin Tan1, Wei Xian1
1Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, People's Republic of China.
Insights
Irbesartan protects diabetic rats from heart damage by inhibiting the RIP1-RIP3-MLKL necroptosis pathway. This study reveals a novel mechanism for irbesartan
Area of Science:
- Cardiovascular Research
- Diabetology
- Molecular Biology
Background:
- Diabetic cardiomyopathy (DCM) is linked to microvascular issues, renin-angiotensin system (RAS) activation, inflammation, and apoptosis.
- Irbesartan, an angiotensin II receptor blocker, is known to affect the RAS, but its precise mechanism in DCM remains unclear.
Purpose of the Study:
- To investigate the expression of the RIP1-RIP3-MLKL necroptosis pathway in the myocardium of diabetic rats.
- To evaluate the protective effects of irbesartan on myocardial damage in a diabetic rat model.
Main Methods:
- 30 Sprague-Dawley rats were divided into control, high glucose/high caloric, diabetes mellitus (4 and 8 weeks), and irbesartan-treated diabetic groups.
- Evaluated cardiac function, inflammatory injury, myocardial histology, and expression of RIP1, RIP3, and MLKL at mRNA and protein levels.
Main Results:
- Diabetes progression worsened cardiac function, increased heart weight to body weight ratio, and elevated myocardial RIP1, RIP3, and MLKL expression.
- Irbesartan treatment improved cardiac function, reduced inflammation, decreased heart weight to body weight ratio, and attenuated myocardial fibrosis.
- The cardioprotective effects of irbesartan correlated with reduced myocardial RIP1, RIP3, and MLKL mRNA and protein levels.
Conclusions:
- Irbesartan demonstrates a significant cardioprotective effect in diabetic rats.
- The mechanism of irbesartan's protection may involve the inhibition of the RIP1-RIP3-MLKL necroptosis pathway in the diabetic heart.
Background:
Diabetic cardiomyopathy (DCM) is strongly linked to microvascular disease, renin-angiotensin system (RAS) activation, cardiac inflammation and cell apoptosis. Irbesartan is an angiotensin II (Ang II) receptor antagonist in RAS system, which inhibited the conversion of Ang I into Ang II, while the specific mechanism is still obscure.
Objective:
This study aims to investigate the expressions necroptosis RIP1-RIP3-MLKL pathway in myocardium of diabetic rats, and the protective action of irbesartan on myocardial damage.
Materials And Methods:
In our study, 30 Sprague-Dawley rats were divided into 5 groups: CON4W, high glucose and high caloric (HC4W), diabetes mellitus 4 weeks (DM4W group), diabetes mellitus 8 weeks (DM8W group), and irbesartan diabetes 8 weeks (Ir DM8W group).
Results:
We discovered that as diabetes progresses, the rats gradually lost weight, the HW/BW ratio were increased gradually, and the cardiac function became worse accompanied with the aggravation of inflammatory injury. Meanwhile, the myocardial fibers and cells were disordered, and the expression of positive substances, RIP1 and RIP3 increased significantly. The mRNA and protein levels of myocardial RIP1, RIP3 and MLKL were all increased with the progression of DM. After the intervention of irbesartan in diabetic rats, the cardiac function was improved, whereas inflammatory injury and HW/BW ratio were decreased. Also, the myocardial fibrosis injury was attenuated, and the PAS positive substances, RIP1 and RIP3 were significantly decreased. The curative effect of irbesartan was related to decreased myocardial RIP1, RIP3 and MLKL mRNA and protein levels.
Conclusion:
In conclusion, irbesartan has a cardioprotective effect on the diabetic rats, and its mechanism may be connected with inhibition of RIP1-RIP3-MLKL pathway.
