CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries

The regulation of arterial tone is critical in the spatial and temporal control of cerebral blood flow. Voltage-gated Ca²⁺ (Ca_V) channels are key regulators of excitation–contraction coupling in arterial smooth muscle, and thereby of arterial tone. Although L- and T-type Ca_V channels have been identified in rodent smooth muscle, little is known about the expression and function of specific Ca_V subtypes in human arteries. Here, we determined which Ca_V subtypes are present in human cerebral arteries and defined their roles in determining arterial tone. Quantitative polymerase chain reaction and Western blot analysis, respectively, identified mRNA and protein for L- and T-type channels in smooth muscle of cerebral arteries harvested from patients undergoing resection surgery. Analogous to rodents, Ca_V1.2 (L-type) and Ca_V3.2 (T-type) α₁ subunits were expressed in human cerebral arterial smooth muscle; intriguingly, the Ca_V3.1 (T-type) subtype present in rodents was replaced with a different T-type isoform, Ca_V3.3, in humans. Using established pharmacological and electrophysiological tools, we separated and characterized the unique profiles of Ca²⁺ channel subtypes. Pressurized vessel myography identified a key role for Ca_V1.2 and Ca_V3.3 channels in mediating cerebral arterial constriction, with the former and latter predominating at higher and lower intraluminal pressures, respectively. In contrast, Ca_V3.2 antagonized arterial tone through downstream regulation of the large-conductance Ca²⁺-activated K⁺ channel. Computational analysis indicated that each Ca²⁺ channel subtype will uniquely contribute to the dynamic regulation of cerebral blood flow. In conclusion, this study documents the expression of three distinct Ca²⁺ channel subtypes in human cerebral arteries and further shows how they act together to orchestrate arterial tone.     

Genome-wide analysis of the emerging infection with Mycobacterium avium subspecies paratuberculosis in the Arabian camels (Camelus dromedarius)

Mycobacterium avium subspecies paratuberculosis (M. ap) is the causative agent of paratuberculosis or Johne's disease (JD) in herbivores with potential involvement in cases of Crohn's disease in humans. JD is spread worldwide and is economically important for both beef and dairy industries. Generally, pathogenic ovine strains (M. ap-S) are mainly found in sheep while bovine strains (M. ap-C) infect other ruminants (e.g. cattle, goat, deer), as well as sheep. In an effort to characterize this emerging infection in dromedary/Arabian camels, we successfully cultured M. ap from several samples collected from infected camels suffering from chronic, intermittent diarrhea suggestive of JD. Gene-based typing of isolates indicated that all isolates belong to sheep lineage of strains of M. ap (M. ap-S), suggesting a putative transmission from infected sheep herds. Screening sheep and goat herds associated with camels identified the circulation of this type in sheep but not goats. The current genome-wide analysis recognizes these camel isolates as a sub-lineage of the sheep strain with a significant number of single nucleotide polymorphisms (SNPs) between sheep and camel isolates (～1000 SNPs). Such polymorphism could represent geographical differences among isolates or host adaptation of M. ap during camel infection. To our knowledge, this is the first attempt to examine the genomic basis of this emerging infection in camels with implications on the evolution of this important pathogen. The sequenced genomes of M. ap isolates from camels will further assist our efforts to understand JD pathogenesis and the dynamic of disease transmission across animal species.     

HIRA directly targets the enhancers of selected cardiac transcription factors during in vitro differentiation of mouse embryonic stem cells

Molecular Biology Reports - HIRA is a histone chaperone known to modulate gene expression through the deposition of H3.3. Conditional knockout of Hira in embryonic mouse hearts leads to...     

C242T polymorphism of NADPH oxidase p22phox gene reduces the risk of coronary artery disease in a random sample of Egyptian population

The p22phox protein subunit is essential for NADPH oxidase activity. The prevalence of C242T variants of p22phox gene was studied in 101 healthy Egyptian controls and 104 acute myocardial infarction (AMI) Egyptian patients. Contribution of oxidative stress, represented by serum oxidized-LDL (ox-LDL), in development of AMI was also examined and correlated with C242T gene variants. Genotyping and ox-LDL were assessed by PCR–RFLP and ELISA. Results showed that wild type CC genotype is prevalent in 27 % of controls; CT and TT are in 72 and 1 %. In patients, the distribution was 40.2, 59.8 and 0 % for CC, CT and TT; respectively, showing a significant difference (p = 0.0259). Serum ox-LDL levels were higher in patients than controls (p ≤ 0.0001). Subjects having CT genotype had lower levels of ox-LDL than CC genotype (p ≤ 0.005). C242T polymorphism of p22phox gene of NADPH oxidase is a novel genetic marker associated with reduced susceptibility to AMI.