Altered redox homeostasis and signaling in Cerebral Cavernous Malformation disease: towards a complex but unifying pathogenic mechanism and therapeutic implications

Abstract

Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease of genetic origin affecting 0.3-0.5% of the population and still awaiting therapies other than neurosurgery. It is characterized by abnormally enlarged and leaky capillaries, which predispose to seizures, neurological deficits and intracerebral hemorrhage (ICH), and may occur sporadically or is dominantly inherited with incomplete penetrance and variable expressivity. Three disease genes have been identified, KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), whose loss-of-function mutations are major pathogenic determinants, accounting for the main phenotypic hallmarks of CCM disease, including destabilization of endothelial cell-cell junctions and increased vascular permeability [1]. However, accumulating evidence in animal models clearly demonstrate that homozygous loss of CCM genes is not fully sufficient to cause CCM lesion formation and disease progression, suggesting the necessary contribution of additional determinants, including microenvironmental stress events [1]. Indeed, the clinical behavior in individual patients, including development of numerous and large lesions, and risk of ICH, remains highly unpredictable, while novel pharmacological strategies are particularly needed to limit disease progression and severity in susceptible individuals [1]. Useful insights into innovative approaches for CCM disease prevention and treatment are emerging from a growing understanding of the biological functions of the three known CCM proteins. Previously, we found that CCM proteins, including KRIT1, play an important role in maintaining intracellular redox homeostasis through the modulation of master regulators of ROS production/detoxification and cell responses to oxidative stress, thereby limiting altered redox signaling and oxidative damage, and preserving cellular resistance to oxidative stress [1-3]. Consistently, recently we demonstrated that KRIT1 loss-of-function causes upregulation of NADPH oxidase-mediated redox signaling, leading to enhanced endothelial cell sensitivity to oxidative stress and inflammation, and decreased microvessel barrier function, further suggesting that altered redox signaling and oxidative stress contribute to CCM pathogenesis [4]. Moreover, preliminary results indicate that these events involve also carbonyl compounds generated through the lipid peroxidation process, and a sustained upregulation of Nrf2, suggesting a complex but unifying pathogenic mechanism that reconciles both the pleiotropic functions of CCM proteins and the distinct therapeutic approaches proposed so far. In addition, we identified genetic modifiers influencing disease severity, including polymorphisms in genes related to inter-individual variability in susceptibility to oxidative stress [5]. Taken together, our findings point to a major role for altered redox signaling in CCM pathogenesis and indicate that inter-individual variability in cell responses to oxidative stress may impact disease onset, progression and severity, suggesting novel preventive and therapeutic approaches.