Prostaglandin F 2 ␣, but Not Latanoprost, Increases the Ca 2؉ Sensitivity of the Pig Iris Sphincter Muscle

PURPOSE. To determine the mechanisms underlying prostaglandin (PG) F 2 ␣-, carbachol (CCh)-, or latanoprost (a PGF 2 ␣ analogue)-induced contraction of the pig iris sphincter muscle. METHODS. Effects of these agents on myofilament Ca 2ϩ sensitivity were evaluated and compared with the use of receptorcoupled permeabilized preparations by ␣-toxin. The effects of PGF 2 ␣ and CCh on the phosphorylation of myosin light chain (MLC) were also analyzed. RESULTS. In the intact strips, all three of these agents induced contractions. CONCLUSIONS. PGF 2 ␣, but not latanoprost, induced Ca 2ϩ sensitization of the pig iris sphincter muscle in an MLC phosphorylation-dependent manner through the rho-rho kinase pathway. The effect of latanoprost on the Ca 2ϩ sensitization mechanism was different from that of PGF 2 ␣ and was thought to play a beneficial role in glaucoma treatment. (Invest Ophthalmol Vis Sci

Purinergic P2Y(6) receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II

Reduced FOXO1 Expression Accelerates Skin Wound Healing and Attenuates Scarring

The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1 +/- mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a-/- mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1+/- mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring

Meiji at 150 Podcast, Episode 038, Dr. Katsuya Hirano (University of California-Los Angeles)

In this episode, Dr. Hirano recounts Japanese settler colonization of Hokkaidō during the Meiji Period, underlining the racialization and dispossession of indigenous Ainu inhabitants. We discuss the role of capitalism and infrastructural development in Japanese imperial expansion, the impacts of the Meiji Restoration on the Ainu population, conditions for Ainu today, and the challenges of cultural commodification.Arts, Faculty ofHistory, Department ofNon UBCUnreviewedFacult