High Glucose Attenuates Cardioprotective Effects of Glucagon-Like Peptide-1 Through Induction of Mitochondria Dysfunction via Inhibition of β-Arrestin-Signaling

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. beta-arrestin is one of the two main downstream effectors of GLP-1 and beta-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 beta-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 beta-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 beta-arrestin plays a key role in GLP-1 resistance: beta-arrestin expression is notably downregulated in high glucose condition and cardioprotective effects of GLP-1 can be diminished by downregulation of beta-arrestin in normal glucose condition while upregulation of beta-arrestin can restore cardioprotective effects of GLP-1 in high glucose condition. Then we explore how beta-arrestin affects the cardioprotective effects of GLP-1 and found that beta-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 beta-arrestin expression, caused mitochondria dysfunction and eventually cell death. Our study provided a new perspective in treating myocardial ischemia/reperfusion injury in diabetic patients.

Automated summary

The study identified that in high glucose conditions, beta-arrestin resistance leads to increased vulnerability of cardiomyocytes, partly due to disruption of the beta-arrestin signaling pathway.