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Bradykinin-(1-9) mitigates autophagy through upregulating PI3K/Akt in rats with myocardial infarction
Lin Lu1, Dai-Xu Li2, Wei Chen3
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, China; Department of Cardiovascular Medicine, the Third Affiliated Hospital of Shandong First Medical University, Jinan, 250031, Shandong Province, China.
Insights
Bradykinin-(1-9) protects the heart after myocardial infarction by reducing cardiac dysfunction, fibrosis, and autophagy. This cardioprotective effect involves the PI3K/Akt pathway, offering new therapeutic insights.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- The precise cardioprotective mechanisms of bradykinin-(1-9) following myocardial infarction (MI) remain incompletely understood.
- Myocardial infarction triggers detrimental processes including cardiac dysfunction, fibrosis, and excessive autophagy in cardiomyocytes.
- Understanding the molecular pathways involved is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the effects of bradykinin-(1-9) on cardiac function, fibrosis, and autophagy in a rat model of myocardial infarction.
- To elucidate the underlying molecular mechanisms, particularly the involvement of the PI3K/Akt pathway and bradykinin B2 receptors.
Main Methods:
- Rats were administered bradykinin-(1-9), the B2 receptor antagonist HOE140, or a combination therapy via osmotic minipumps prior to inducing myocardial infarction.
- Myocardial infarction was induced by ligating the left anterior descending coronary artery.
- Cardiac function was assessed using echocardiography, and cardiac tissues were analyzed for fibrosis and autophagy markers after two weeks.
Main Results:
- Bradykinin-(1-9) treatment significantly attenuated left ventricular dysfunction and reduced cardiac fibrosis and autophagy in rats post-myocardial infarction.
- The protective effects of bradykinin-(1-9) were partially reversed by co-administration of the B2 receptor blocker HOE140.
- Inhibition of autophagy by bradykinin-(1-9) was partially reversed by the PI3K inhibitor LY294002, indicating a role for the PI3K/Akt pathway.
Conclusions:
- Bradykinin-(1-9) exerts significant cardioprotective effects against myocardial infarction-induced damage.
- The mechanism involves the inhibition of cardiomyocyte autophagy through the upregulation of the PI3K/Akt signaling pathway.
- Targeting bradykinin-(1-9) and the PI3K/Akt pathway may represent a promising therapeutic approach for managing myocardial infarction.
Abstract:
The cardioprotective mechanisms of bradykinin-(1-9) in myocardial infarction were unclear. We investigated the effect of bradykinin-(1-9) on cardiac function, fibrosis, and autophagy induced by myocardial infarction and identified the mechanisms involved. To investigate the cardioprotective effect of bradykinin-(1-9), various doses of bradykinin-(1-9), its B2 receptor blocker HOE140, or their combination were administered to rats via subcutaneous osmotic minipump implantation before myocardial infarction. After 2 days, myocardial infarction was induced by ligation of the left anterior descending coronary artery. After 2 weeks, echocardiographic measurements and euthanasia were performed. Bradykinin-(1-9) treatment attenuated left ventricular dysfunction, fibrosis, and autophagy in rats with myocardial infarction, which was partially reversed by HOE140 administration. Moreover, the downregulatory effect of bradykinin-(1-9) on autophagy was partially reversed by combination with the PI3K inhibitor LY294002. Thus, bradykinin-(1-9) inhibits myocardial infarction-induced cardiomyocyte autophagy by upregulating the PI3K/Akt pathway.
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