Cardiac Nonmyocyte Cell Functions and Crosstalks in Response to Cardiotoxic Drugs

Figures

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  Figure 1. The vicious cycle of ROS production in cardiac fibroblast. DOX induces ROS production that mediates the activation of TGF-β through its release from LAP. Through its paracrine action, TGF-β induces expression of genes involved in oxidative stress, NOX2, and NOX4, promoting the further increase of ROS.

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  Figure 2. Effects of anticancer drugs that induce oxidative stress on endothelial cells. Trastuzumab inhibits HER2/4 pathway, blocking activation of AKT and its regulatory effect on mitochondrial respiration, with consequent ROS accumulation. The latter causes the inhibition of eNOS activity. DOX, is able to directly bind eNOS, inhibiting NO production and inducing RNS and ROS accumulation.

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  Figure 3. A functional crosstalk between cardiac cells, affecting by cardiotoxic drugs. (a) In response to physiological stress, endothelial cells secrete survival factors, NRG1. NRG1 acts on HER2/HER4 in cardiomyocytes, inducing survival pathways, blocking ROS production, and favoring NO release. Cardiac fibroblasts produce components of extracellular matrix to ensure appropriate heart architecture also in response to changes in cardiac homeostasis. (b)The defensive mechanism mediated by NRG1 does not occur in presence of trastuzumab. Moreover, the oxidative stress induced by anticancer drugs, such as DOX or trastuzumab, induces activation of NFκB in the endothelium, with an expression of proinflammatory cytokines, IL-2 and IL-6, activating immune cells. The activated immune cells promote a profibrotic phenotype of fibroblasts, with abnormal deposition of extracellular matrix and pathological cardiac remodeling.