Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow

Abstract

Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions.

MicroRNA‐194 reduces inflammatory response and human dermal microvascular endothelial cells permeability through suppression of TGF‐β/SMAD pathway by inhibiting THBS1 in chronic idiopathic urticaria

“…27 It was previously reported that an uncommon urticaria-like neutrophilic dermatosis serves as a sign of the presence of IgA myeloma. 37 What worth mentioning is that from the screen of relative gene and prediction of miRNA, we found that miR-194 could regulate THBS1, thereby regulating the TGF-β and influencing the development of CIU. IgG is a main choice of cancer treatment, particularly in patients with metastatic or advanced cancers.…”

A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

“…The reduction in cGMP levels we observed in partially CD36 deficient AA women is opposite to what would be predicted based on the in vitro inhibition of the NO-sGC pathway by TSP1-CD36 engagement. However, TSP1 can potently inhibit vascular NO signaling via its other receptor CD47, and CD36 deletion might enhance TSP1 availability for binding CD47 (22,23,34). Possibly CD36 binding TSP1 buffers the more potent inhibitory effect on TSP1 signaling via CD47.…”

“…This receptor is abundant in vascular endothelial cells, especially in heart, skeletal muscle and adipose tissue (17) where it facilitates highaffinity tissue FA uptake (18,19) and cellular FA metabolism (20). TSP1 binding to CD36 (21,22) or its other receptor CD47 (23) suppresses NO-cGMP signaling in cultured endothelial cells but whether CD36 contributes to NO-mediated vascular effects in vivo remains unknown. In the present study, we tested the hypothesis that the G allele of CD36 coding SNP rs3211938 (G/T), which is 10-times more common in AA (genotype frequency of ϳ20%) as compared to Caucasians and results in ϳ50% reduced CD36 expression (24) would associate with altered endothelial function (Protocol 1).…”

Platelet hyperaggregability in patients with atrial fibrillation

“…TSP-1 also inhibits non-NO activation of sGC [23]. TSP-1 has been implicated as a contributor to platelet hyperaggregability [13], although the potential importance of this relationship has not been previously reported in patients with AF.…”