Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro-oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

 

Comments:

The passage you provided discusses research findings related to the side effects of cancer chemotherapy, specifically focusing on the impact on vital organ systems such as the liver and heart. Here's a summary of the key points:

1. **Problem**: Chemotherapy can cause damage to vital organ systems, limiting its clinical use. The mechanisms behind this chemotherapy-induced damage, particularly in the heart and liver, are not well understood.

2. **Observation**: In patients with a history of chemotherapy, there was an increase in the expression of a G protein regulator called RGS7 and a decrease in R7 family member RGS11 in the liver.

3. **Experimental Intervention**: Knocking down RGS7 using a specific technique (RGS7 shRNA) reduced chemotherapy-induced liver damage significantly, including collagen and lipid deposition, glycogen accumulation, and elevated liver enzymes.

4. **Surprising Finding**: Decreasing RGS7 levels in the heart (by introducing RGS7 shRNA directly to the myocardium) had a similar positive effect on the liver, despite not directly affecting RGS7 levels in the liver.

5. **Mechanism**: Chemotherapy-affected heart cells release signaling molecules (endocrine factors) like transforming growth factor β1 (TGFβ1) and follistatin-related protein 1 (FSTL1). RGS7 overexpression in the heart reproduced the effects of chemotherapy on the liver.

6. **Impact of TGFβ1 Signaling**: Inhibition of TGFβ1 signaling using a specific blocker reduced the adverse effects of cardiac RGS7 overexpression on the liver. This indicates that RGS7 controls the release of TGFβ1 from the heart and its harmful effects on the liver, emphasizing the significance of cardiokine signaling in chemotherapy-induced multiorgan damage.

In essence, the research suggests that RGS7 plays a crucial role in mediating the damaging effects of chemotherapy on vital organs, particularly the liver, through the regulation of TGFβ1 signaling. Understanding these mechanisms could potentially lead to the development of targeted therapies to mitigate the side effects of chemotherapy on organ systems.