Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease, with a prevalence of 0.3%-0.5% in the general population, characterized by closely clustered, abnormally dilated and leaky capillary channels (caverns). These can be single or multiple and may cause serious clinical symptoms, including recurrent headaches, neurological deficits, seizures, stroke, and fatal intracerebral hemorrhage. To date, there are not direct therapeutic approaches for CCM disease, besides the surgical removal of accessible lesions. CCM is a disease of proven genetic origin (OMIM 116860) that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Genetic studies have so far identified three genes whose mutation causes CCM: KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3). Comprehensive studies in cellular and animal models have revealed a major role for these genes in blood vessel formation and maintenance, showing a causal link between their loss-of-function mutations and the hyperactivation of the RhoA GTPase, which destabilizes endothelial barrier function. However, the mechanisms of CCM pathogenesis remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of CCM genes is not sufficient to induce CCM lesions, suggesting that additional factors, possibly specific for the neurovascular microenvironment, might be necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage through an antioxidant pathway involving FoxO1 and SOD2. Here, we report novel findings showing that KRIT1 loss-of-function causes a ROS-dependent upregulation of transcription factors involved in oxidative stress-mediated endothelial cell dysfunctions, providing novel insights into the understanding of KRIT1 functions, and suggesting that the onset of CCM disease may result from impaired endothelial cell defenses against local oxidative stress events occurring at specific cerebrovascular districts sensitized by CCM gene mutations.
KRIT1 loss-of-function causes a ROS-dependent upregulation of transcription factors involved in oxidative stress responses
GOITRE, Luca;DE LUCA, Elisa;MOGLIA, Andrea;RETTA, Saverio Francesco
2013-01-01
Abstract
Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease, with a prevalence of 0.3%-0.5% in the general population, characterized by closely clustered, abnormally dilated and leaky capillary channels (caverns). These can be single or multiple and may cause serious clinical symptoms, including recurrent headaches, neurological deficits, seizures, stroke, and fatal intracerebral hemorrhage. To date, there are not direct therapeutic approaches for CCM disease, besides the surgical removal of accessible lesions. CCM is a disease of proven genetic origin (OMIM 116860) that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Genetic studies have so far identified three genes whose mutation causes CCM: KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3). Comprehensive studies in cellular and animal models have revealed a major role for these genes in blood vessel formation and maintenance, showing a causal link between their loss-of-function mutations and the hyperactivation of the RhoA GTPase, which destabilizes endothelial barrier function. However, the mechanisms of CCM pathogenesis remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of CCM genes is not sufficient to induce CCM lesions, suggesting that additional factors, possibly specific for the neurovascular microenvironment, might be necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage through an antioxidant pathway involving FoxO1 and SOD2. Here, we report novel findings showing that KRIT1 loss-of-function causes a ROS-dependent upregulation of transcription factors involved in oxidative stress-mediated endothelial cell dysfunctions, providing novel insights into the understanding of KRIT1 functions, and suggesting that the onset of CCM disease may result from impaired endothelial cell defenses against local oxidative stress events occurring at specific cerebrovascular districts sensitized by CCM gene mutations.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
