"Investigation of the Protective Effect of HO-1 in Human iPSC-Derived Cardiomyocytes"

Heme oxygenase-1 (HO-1) is an inducible enzyme with antioxidant and cytoprotective properties that degrades heme into carbon monoxide (CO), ferrous ions (Fe2+), and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. HO-1 is activated by cellular stress and plays a role in mitigating oxidative damage. HO-1 can be expressed primarily by its substrate, free heme, and also by a wide variety of stimuli, inducing hypoxia, hyperoxia, pro-inflammatory cytokines, nitric oxide (NO), heavy metals, ultraviolet radiation, heat shock, shear stress, and hydrogen peroxide. This adaptive response of HO-1 to these cytotoxic stimuli implies that HO-1, besides its role in heme degradation, may function as a critical cytoprotective molecule. Understanding HO-1's protective mechanisms could inform the development of novel strategies to prevent or attenuate myocardial damage, particularly in contexts like anthracycline-induced cardiotoxicity, where oxidative stress plays a central role. HO-1 has potential in reducing doxorubicin-induced cardiotoxicity, which is heart damage resulting from certain cancer treatments. Investigation of HO-1's potentially protective effects against oxidative stress was performed by using two pairs of human induced pluripotent stem cell (iPSC) lines: CTRL, HO-1 knockout; and LV GFP, LV HO-1 overexpression – combined with expression of GFP and luciferase. iPSCs were differentiated into cardiomyocytes, and exposed to various stressors, including hydrogen peroxide, hypoxia and doxorubicin treatment, to evaluate HO-1 importance in protection against induced oxidative stress. We assumed that cells deficient in HO-1 will exhibit reduced antioxidant responses to oxidative stress, leading to higher mortality rates. Our findings indicate that HO-1 deficiency increases sensitivity and mortality, while overexpression of HO-1, despite being generally protective, can be detrimental if excessively high. Therefore, balanced HO-1 levels are crucial for cell survival. This research highlights the dual role of HO-1 in protecting and potentially harming Cardiomyocytes by supplementing iron which could accelerate ferroptosis.