Stimulation of adenosine A 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 receptor (AR) on cardiac protection during oxidative stress have remained elusive. In this study, we found that stimulation of ARs with N-cyclopentyladenosine (CPA), a specific AR agonist, attenuated the HO-induced intracellular and mitochondrial reactive oxygen species (ROS) production and apoptosis. In addition, AR 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 Gβγ subunit of heterotrimeric Gα protein antagonized AR-mediated antioxidant and antiapoptotic effects, confirming the potential role of Gβγ subunit-mediated AR signaling. Additionally, cardioprotective effects of CPA mediated through PI3K/Akt- and ERK1/2-dependent signaling pathways. Thus, we propose that AR represents a promising therapeutic target for prevention of oxidative injury in the heart.