PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy.

Abstract

Doxorubicin (Doxo) is an effective agent commonly used in cancer therapeutics. Unfortunately, Doxo treatment can stimulate cardiomyopathy and subsequent heart failure, limiting the use of this drug. The role of phosphatase and tensin homolog (PTEN) in apoptosis has been documented in Doxo-induced cardiomyopathy (DIC) and heart failure models. However, whether direct inhibition of PTEN attenuates apoptosis, cardiac remodeling, and inflammatory M1 macrophages in the DIC model remains elusive. Therefore, the present study was designed to understand the effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At day 56, echocardiography was performed, which showed that VO treatment significantly ( P < 0.05) improved heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, proinflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data show a significant increase in apoptosis, hypertrophy, fibrosis, and proinflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and proinflammatory M1 macrophages significantly ( P < 0.05) compared with the Doxo-treated group. Western blot analysis confirmed the reduction of phosphorylated PTEN and increase in phosphorylated AKT protein expression in the Doxo + VO-treated group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggest that VO treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through the PTEN/AKT pathway, resulting in improved heart function in DIC. NEW & NOTEWORTHY Doxorubicin-induced cardiomyopathy (DIC) is still a major issue in patients with cancer. These novel findings on the phosphatase and tensin homolog inhibitor VO-OHpic in DIC is the first report, as per the best of our knowledge, that VO-OHpic significantly decreases apoptosis, fibrosis, hypertrophy, adverse cardiac remodeling, and proinflammatory M1 macrophages and increases anti-inflammatory M2 macrophages along with significantly improved cardiac function. VO-OHpic could be a future therapeutic agent for patients with DIC.