Stimulation of adenosine A1 receptor prevents oxidative injury in H9c2 cardiomyoblasts: Role of Gβγ-mediated Akt and ERK1/2 signaling

Oxidative stress causes cellular injury and damage in the heart primarily through apoptosis resulting in cardiac abnormalities such as heart failure and cardiomyopathy. During oxidative stress, stimulation of adenosine receptor (AR) has been shown to protect against oxidative damage due to their cytoprotective properties. However, the subtype specificity and signal transductions of adenosine A(1) receptor (A(1)R) on cardiac protection during oxidative stress have remained elusive. In this study, we found that stimulation of A(1)Rs with N-6-cyclopentyladenosine (CPA), a specific A1R agonist, attenuated the H2O2-induced intracellular and mitochondrial reactive oxygen species (ROS) production and apoptosis. In addition, A(1)R stimulation upregulated the synthesis of antioxidant enzymes (catalase and GPx-1), antiapoptotic proteins (Bcl-2 and Bcl-xL), and mitochondria-related markers (UCP2 and UCP3). Blockades of G beta gamma subunit of heterotrimeric G alpha(i) protein antagonized A(1)R-mediated antioxidant and antiapoptotic effects, confirming the potential role of G beta gamma subunit-mediated A(1)R signaling. Additionally, cardioprotective effects of CPA mediated through PI3K/Akt- and ERK1/2-dependent signaling pathways. Thus, we propose that A(1)R represents a promising therapeutic target for prevention of oxidative injury in the heart.

Automated summary

This study demonstrates that stimulation of A(1)Rs can attenuate oxidative stress-induced damage in heart cells, upregulate synthesis of antioxidant enzymes and antiapoptotic proteins, and exert cardioprotective effects through G beta gamma subunit-mediated A(1)R signaling pathway as well as PI3K/Akt and ERK1/2-dependent pathways.