ABSTRACT
Thoracic aortic aneurysm (TAA) predisposes to sudden, life-threatening aortic dissection. The factors that regulate interindividual variability in TAA severity are not well understood. Identifying a molecular basis for this variability has the potential to improve clinical risk stratification and advance mechanistic insight. We previously identified COQ8B, a gene important for biosynthesis of coenzyme Q, as a candidate genetic modifier of TAA severity. Here, we investigated the physiological role of COQ8B in human aortic smooth muscle cells (SMCs) and further tested its genetic association with TAA severity. We find COQ8B protein localizes to mitochondria in SMCs, and loss of mitochondrial COQ8B leads to increased oxidative stress, decreased mitochondrial respiration, and altered expression of SMC contractile genes. Oxidative stress and mitochondrial cristae defects were prevalent in the medial layer of human proximal aortic tissues in patients with TAA, and COQ8B expression was decreased in TAA SMCs compared with controls. A common single nucleotide polymorphism (SNP) rs3865452 in COQ8B (c.521A>G, p.H174R) was associated with decreased rate of aortic root dilation in young patients with TAA. In addition, the SNP was less frequent in a second cohort of early-onset thoracic aortic dissection cases compared with controls. COQ8B protein levels in aortic SMCs were increased in TAA patients homozygous for rs3865452 compared with those homozygous for the reference allele. Thus, COQ8B is important for aortic SMC metabolism, which is dysregulated in TAA, and rs3865452 may decrease TAA severity by increasing COQ8B level. Genotyping rs3865452 may be useful for clinical risk stratification and tailored aortopathy management.
ABSTRACT
Animal models suggest that the endocannabinoid system (eCS) helps regulate various aspects of social behavior, including play behavior and social reward, during adolescence. Properly tuned endocannabinoid signaling may be a critical developmental component in the emergence of normal adult sociability. In the current experiment, we attempted to pharmacologically disrupt endocannabinoid tone during early adolescence, and then measure the behavioral effects at two subsequent time points. 36 male and 36 female Long Evans rats received daily injections of one of three treatments between post-natal day (PND) 25-39: 1) vehicle treatment, 2) 0.4 mg/kg CP55,940 (a potent CB1/CB2 receptor agonist), or 3) 0.5 mg/kg AM251 (a CB1 receptor antagonist/inverse agonist). Both soon after treatment (PND 40-44) and several weeks later (PND 66-70), subjects were tested in an elevated plus maze (EPM) for anxiety and in a three-chambered apparatus for sociability. For the latter test, the number of entries into each chamber and the amount of time spent investigating each target were measured. Analyses revealed significant main effects of both sex and age on sociability: males expressed greater sociability compared to females, and sociability was higher in adolescence than adulthood. Most importantly, drug treatment (both CP55,940 and AM251) attenuated sociability in adolescence without having a significant effect on anxiety in the EPM. However, this effect did not persist into adulthood. These results indicate that pharmacological disruption of endocannabinoid tone - through either chronic agonism or antagonism of cannabinoid receptors - during early adolescence has a detrimental effect on sociability. This effect may be caused by transient, compensatory alterations in the eCS.
