Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.

Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/ß-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

Caffeine attenuates metabolic syndrome in diet-induced obese rats.

OBJECTIVE: Caffeine is a constituent of many non-alcoholic beverages. Pharmacological actions of caffeine include the antagonism of adenosine receptors and the inhibition of phosphodiesterase activity. The A1 adenosine receptors present on adipocytes are involved in the control of fatty acid uptake and lipolysis. In this study, the effects of caffeine were characterized in a diet-induced metabolic syndrome in rats. METHODS: Rats were given a high-carbohydrate, high-fat diet (mainly containing fructose and beef tallow) for 16 wk. The control rats were given a corn starch diet. Treatment groups were given caffeine 0.5 g/kg of food for the last 8 wk of the 16-wk protocol. The structure and function of the heart and the liver were investigated in addition to the metabolic parameters including the plasma lipid components. RESULTS: The high-carbohydrate, high-fat diet induced symptoms of metabolic syndrome, including obesity, dyslipidemia, impaired glucose tolerance, decreased insulin sensitivity, and increased systolic blood pressure, associated with the development of cardiovascular remodeling and non-alcoholic steatohepatitis. The treatment with caffeine in the rats fed the high-carbohydrate, high-fat diet decreased body fat and systolic blood pressure, improved glucose tolerance and insulin sensitivity, and attenuated cardiovascular and hepatic abnormalities, although the plasma lipid concentrations were further increased. CONCLUSION: Decreased total body fat, concurrent with increased plasma lipid concentrations, reflects the lipolytic effects of caffeine in adipocytes, likely owing to the caffeine antagonism of A1 adenosine receptors on adipocytes.