Abstract
An increased vulnerability has been detected after ischemia/reperfusion injury in cardiomyocytes in diabetic patients. Glucagon-like peptide-1 (GLP-1) has been proven to have a notable cardioprotective effect in cardiomyocytes. However, in diabetic patients, the cardioprotective effects of GLP-1 are compromised, which is called GLP-1 resistance. β-arrestin is one of the two main downstream effectors of GLP-1 and β-arrestin signaling pathway exerts cardioprotective effects upon activation of GLP-1R. Our hypothesis is that the increased vulnerability of cardiomyocytes in diabetic patients is partly due to disruption of the β-arrestin signaling pathway. To test this, we analyzed cardiomyocyte viability and survival in high glucose and normal glucose condition after hypoxia/reoxygenation injury in vitro, additional GLP-1 was used to determine whether β-arrestin signaling pathway was involved. We also investigated the role of mitochondrial dysfunction in GLP-1 resistance. Our results showed that cardioprotective effects of GLP-1 were reduced in high glucose cultured H9C2 cells compared to normal glucose cultured H9C2, verifying the existence of GLP-1 resistance in high glucose cultured H9C2 cells. Further study suggested that β-arrestin plays a key role in GLP-1 resistance: β-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of β-arrestin in normal glucose condition while upregulation of β-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how β-arrestin affects the cardioprotective effects of GLP-1 and found that β-arrestin exerts cardioprotective effects by improving mitochondria quality control via the PI3K/Akt signaling pathway. Thus, our study found out a new mechanism of GLP-1 resistance of cardiomyocytes in high glucose conditions that impaired β-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.
Highlights
Evidence showed that diabetic patients are two to three times more likely to have cardiovascular disease than non-diabetic patients (Danaei et al, 2006)
Diabetic patients exhibited vulnerable cardiomyocytes when experiencing stress-like ischemia, and Glucagon-like peptide-1 (GLP-1) failed to exert intact cardioprotective effects in diabetic cardiomyocytes
We found that the cardioprotective effects of GLP-1 are notably attenuated in high glucose conditions after H/R injury
Summary
Evidence showed that diabetic patients are two to three times more likely to have cardiovascular disease than non-diabetic patients (Danaei et al, 2006). Cardiovascular complications are the major causes of morbidity and mortality in diabetic patients, among which ischemic heart disease is the leading cause of death (Emerging Risk Factors Collaboration et al, 2010). It has been proven that cardiomyocytes exhibit increased vulnerability in diabetic patients, and myocardial infarction causes more cell death in diabetic patients than in non-diabetic patients (Lopaschuk et al, 2010; Smith et al, 2016). Modern medicine restores myocardial perfusion through either percutaneous coronary intervention or thrombolytic therapy, and both of these have brought about a new problem that aggravates cardiomyocyte damage: ischemia/reperfusion injury (Kolwicz et al, 2013). The mechanisms underlying the increased vulnerability of cardiomyocytes in diabetic patients remained unknown
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