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 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 DIC model remains elusive. Therefore, the current study is designed to understand effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At D56, echocardiography was performed, which shows VO-OHpic treatment significantly (p<0.05) improves heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, pro-inflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data shows a significant increase in apoptosis, hypertrophy, fibrosis, and pro-inflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and pro-inflammatory M1 macrophages significantly (p<0.05) compared to Doxo group. Western blotting confirmed the reduction of p-PTEN and increase in p-AKT protein expression in the Doxo+VO group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggests that VO-OHpic treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through PTEN/AKT pathway, resulting in improved heart function in DIC.

Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

“…In another study, Hadi et al reported that treatment with vitamin E and telmisartan significantly reduces infiltration of monocytes into the heart, thereby reducing the cardiac inflammatory response, relieving DOX-induced cardiac injury and improving cardiac dysfunction [ 37 ]. We and other researchers have reported that DOX treatment promotes imbalance between M1 macrophages and M2 macrophages in mice, and aggravation of this imbalance further aggravates cardiac injury and cardiomyocyte apoptosis [ 7 , 38 ]. These results suggest that DOX-induced immune cell activation plays an important role in myocardial injury.…”

The Acute Effects of 5 Fluorouracil on Skeletal Muscle Resident and Infiltrating Immune Cells in Mice

“…Chemotherapy has been shown to mitigate the in ammatory response with exercise (53,64), induce leukopenia/cytopenia (19), and disrupt cardiacmacrophage in ltration (65). To the best of our knowledge, this is the rst study to demonstrate that chemotherapeutic 5FU has deleterious effects on immune cell abundance in otherwise healthy uninjured skeletal muscle.…”

Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling

“…Pathologically, immune-related adverse events in the setting of ICIs treatment are largely characterized by the infiltration of macrophages into the tissue, causing injury 10 . Recent data suggest the involvement of macrophage polarization in cardiovascular diseases, such as chemotherapy-related cardiac injury 11 . Under some condition, monocytes travel to the site of injury and undergo differentiation into either proinflammatory M1 macrophages or antiinflammatory M2 macrophages 12 .…”