RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis

Das, Kiran; Basak, Madhuri; Mahata, Tarun; Kumar, Manish; Kumar, Dinesh; Biswas, Sayan; Chatterjee, Suvro; Moniruzzaman, Mahammed; Saha, Nimai Chandra; Mondal, Kausik; Kumar, Pranesh; Das, Priyadip; Stewart, Adele; Maity, Biswanath

doi:10.1016/j.redox.2022.102487

Cited by 9 publications

(20 citation statements)

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“…In post‐mortem cardiac tissue isolated from patients with a history of cancer chemotherapy expression of R7 family RGS protein RGS7 is increased 25 while expression of fellow R7 family member RGS11 decreases 24 . We observed an identical pattern in hepatic tissue via both immunohistochemistry (Figure 1A) and western blot (Figure 1B).…”

Section: Resultsmentioning

confidence: 56%

“…23 Recent evidence has also identified RGS11 and RGS7 as bidirectional modulators of CaMKII-dependent cardiotoxicity. 24,25 Here, we demonstrate that chemotherapy exposure is associated with a shift in the ratio of R7 family member RGS7 to RGS11 in isolated cardiac and hepatic cells, tissues isolated from doxorubicin-treated mice, and chemotherapy-exposed human patients. Given prior data demonstrating potent pro-oxidant and pro-apoptotic actions of RGS7 and binding partner Gβ 5 19,25,26 and opposing actions of RGS11, 24 these observations suggest that RGS7/RGS11 might function as key modulators of chemotherapy driven hepatic and cardiac damage.…”

Section: Introductionmentioning

confidence: 70%

“…The ability of RGS7 to promote and RGS11 to suppress doxorubicin-dependent oxidative stress, mitochondrial dysfunction, and apoptosis in myocytes also requires CaMKII. 24,25 While CaMKII can be activated in the absence of Ca 2+ /calmodulin through oxidation at a pair of methionine residues (M281/M282) in the regulatory domain, 54 manipulating RGS7/RGS11 expression had the greatest impact on phosphorylation rather than oxidation. Thus, though RGS7/RGS11 clearly modulate oxidative stress in hepatocytes, they likely control CaMKII activity via yet-to-be-identified but ROS-independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitor doses were chosen to exceed reported IC 50 values for each target, 37,38 while also ensuring minimal off target effects on myocyte viability 39 . Cells were also treated with media containing 10% serum isolated from chemotherapy patients whose hearts had no fibrosis (−Fibrosis) or fibrosis (+Fibrosis) for 16 h as we previously described 24,40 . Human serum containing a complex milieu of cytokines and chemokines secreted into the circulation including factors capable of stimulating intracellular signaling in myocytes 41 .…”

Section: Methodsmentioning

confidence: 99%

“…RGS6 has been detected in both the liver 20 and heart 21,22 and has been implicated in doxorubicin‐induced cardiac damage 23 . Recent evidence has also identified RGS11 and RGS7 as bidirectional modulators of CaMKII‐dependent cardiotoxicity 24,25 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 56%