Effects of a novel hydrogen sulfide prodrug in a porcine model of acute limb ischemia.

OBJECTIVE: Previous studies have shown that hydrogen sulfide (H2S) exerts potent proangiogenic properties under in vitro conditions and in rodent models. We sought to determine whether a novel H2S prodrug promotes peripheral revascularization in a swine model of acute limb ischemia (ALI). METHODS: ALI was induced in 17 female miniswine via intravascular occlusion of the external iliac. At day 7 after ALI induction, miniswine (n = 17) were randomized to received placebo or the H2S prodrug, SG-1002 (800 mg per os twice a day), for 35 days. At day 35 SG-1002 increased circulating levels of H2S (5.0 ± 1.2 µmol/L vs 1.8 ± 0.50 µmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 µmol/L vs 2.6 ± 0.8 µmol/L; P < .05), and nitrite (0.5 ± 0.05 µmol/L vs 0.3 ± 0.03 µmol/L; P < .005) compared with placebo. SG-1002 therapy increased angiographic scoring in ischemic limb vessel number (27.6 ± 1.6 vs 22.2 ± 1.8; P < .05) compared with placebo. Treatment with SG-1002 preserved existing capillaries in ischemic limbs (128.3 ± 18.7 capillaries/mm2 vs 79.0 ± 9.8 capillaries/mm2; P < .05) compared with placebo. Interestingly, treatment with SG-1002 also improved coronary vasorelaxation responses to bradykinin and substance P in miniswine with ALI. CONCLUSIONS: Our results suggest that daily administration of the H2S prodrug, SG-1002, leads to an increase in circulating H2S and nitric oxide signaling and preserves vessel number and density in ischemic limbs. Furthermore, SG-1002 therapy improved endothelial-dependent coronary artery vasorelaxation in the setting of ALI. Our data demonstrate that SG-1002 preserves the vascular architecture in ischemic limbs and exerts vascular protective effects in the coronary vasculature in a model of peripheral vascular disease.

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia.

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

The anatomy of the larynx of the bowhead whale, Balaena mysticetus, and its sound-producing functions.

This study describes the morphology of the laryngeal apparatus in bowhead whales (Balaena mysticetus) with respect to respiration, deglutition, and vocalization. We also examined the intrinsic cricoarytenothyroid muscle (Musculus (M.) diverticuli laryngei) which forms the laryngeal diverticulum, to ascertain its interactions with the laryngeal cartilages during respiration and sound production. Five fetal larynges and four from adult whales were studied using noninvasive imaging, as well as macroscopic and microscopic techniques. The larynx extends from the skull base into the thoracic inlet. The dorsally curved laryngeal stalk, supported by epiglottis and the corniculate processes of arytenoid cartilages, is situated within the nasopharynx. The epiglottic cartilage exhibits a prominent medial ridge. The arytenoid cartilages are rod-shaped, and extend through the laryngeal cavity. The thyroid cartilage possesses a prominent caudal horn with a fibrous articulation to the ventrally incomplete cricoid cartilage. The M. thyroepiglotticus forms the connection between epiglottic and thyroid cartilages. The M. cricothyroideus lateralis connects the caudal horn of the thyroid cartilage with the cricoid cartilage and the M. cricothyroideus medialis connects the cricoid and thyroid cartilage. An extensive laryngeal diverticulum (Diverticulum laryngis), formed by the laryngeal mucosa and M. diverticuli laryngei, is positioned caudo-ventral to the laryngeal vestibule. The mucosa thickens into a fold medial to the vocal processes of the arytenoid cartilages. Experiments with airflow combined with histological and anatomical evidence strongly suggest a sound producing function for these (vocal) folds. This analysis provides the first account of sound producing structures and function in bowhead whales.