The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases

Spermatozoa undergo exocytosis in response to agonists that induce Ca2+ influx and, in turn, activation of phosphoinositidase C, phospholipase C, phospholipase A2, and cAMP formation. Since the role of cAMP downstream of Ca2+ influx is unknown, this study investigated whether cAMP modulates phospholipase C or phospholipase A2 using a ram sperm model stimulated with A23187 and Ca2+. Exposure to dibutyryl-cAMP, phosphodiesterase inhibitors or forskolin resulted in enhancement of exocytosis. However, the effect was not due to stimulation of phospholipase C or phospholipase A2: in spermatozoa prelabelled with [3H]palmitic acid or [14C]arachidonic acid, these reagents did not enhance [3H]diacylglycerol formation or [14C]arachidonic acid release. Spermatozoa were treated with the phospholipase A2 inhibitor aristolochic acid, and dibutyryl-cAMP to test whether cAMP acts downstream of phospholipase A2. Under these conditions, exocytosis did not occur in response to A23187 and Ca2+. However, inclusion of dibutyryl-cAMP and the phospholipase A2 metabolite lysophosphatidylcholine did result in exocytosis (at an extent similar to that seen when cells were treated with A23187/Ca2+ and without the inhibitor). Inclusion of lysophosphatidylcholine alone, without dibutyryl-cAMP, enhanced exocytosis to a lesser extent, demonstrating that cAMP requires a phospholipase A2 metabolite to stimulate the final stages of exocytosis. These results indicate that cAMP may act downstream of phospholipase A2, exerting a regulatory role in the exocytosis triggered by physiological agonists.

Download Full-text

Thromboses and Hemostasis Disorders Associated with Coronavirus Disease 2019: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting

Global Medical Genetics ◽

10.1055/s-0041-1731068 ◽

2021 ◽

Author(s):

Darja Kanduc

Keyword(s):

Immune System ◽

Severe Acute Respiratory Syndrome ◽

Natural Infection ◽

Vascular Diseases ◽

Cross Reactivity ◽

Active Immunization ◽

Thromboembolic Complications ◽

Human Proteins ◽

Almost All

AbstractBy examining the issue of the thromboses and hemostasis disorders associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) through the lens of cross-reactivity, it was found that 60 pentapeptides are shared by SARS-CoV-2 spike glycoprotein (gp) and human proteins that— when altered, mutated, deficient or, however, improperly functioning— cause vascular diseases, thromboembolic complications, venous thrombosis, thrombocytopenia, coagulopathies, and bleeding, inter alia. The peptide commonality has a relevant immunological potential as almost all of the shared sequences are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes, thus supporting the possibility of cross-reactions between the viral gp and the thromboses-related human proteins. Moreover, many of the shared peptide sequences are also present in pathogens to which individuals have previously been exposed following natural infection or vaccinal routes, and of which the immune system has stored imprint. Such an immunological memory might rapidly trigger anamnestic secondary cross-reactive responses of extreme affinity and avidity, in this way explaining the thromboembolic adverse events that can associate with SARS-CoV-2 infection or active immunization.

Download Full-text

Pulmonary Vascular Diseases Associated with Infectious Disease—Schistosomiasis and Human Immunodeficiency Viruses

Clinics in Chest Medicine ◽

10.1016/j.ccm.2020.11.007 ◽

2021 ◽

Vol 42 (1) ◽

pp. 71-80

Author(s):

Ghazwan Butrous

Keyword(s):

Infectious Disease ◽

Vascular Diseases ◽

Human Immunodeficiency Viruses ◽

Pulmonary Vascular Diseases

Download Full-text

Role of phosphodiesterase inhibitors in stent-related symptoms: a systematic review and meta-analysis

World Journal of Urology ◽

10.1007/s00345-019-02862-z ◽

2019 ◽

Vol 38 (4) ◽

pp. 929-938 ◽

Cited By ~ 1

Author(s):

Gopal Sharma ◽

Aditya Prakash Sharma ◽

Ravimohan S. Mavuduru ◽

Sudheer K. Devana ◽

Girdhar Singh Bora ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Phosphodiesterase Inhibitors

Download Full-text

SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling

Circulation Research ◽

10.1161/circresaha.117.310696 ◽

2017 ◽

Vol 121 (6) ◽

pp. 636-649 ◽

Cited By ~ 15

Author(s):

Xiaolong Zhu ◽

Sha Ding ◽

Cong Qiu ◽

Yanna Shi ◽

Lin Song ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Developmental Disorders ◽

Interaction Mechanism ◽

Growth Factor Receptor ◽

Vascular Diseases ◽

Cell Interaction ◽

Protein Signaling

Rationale: The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell–cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. Objective: The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Methods and Results: Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)–deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. Conclusions: These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.

Download Full-text

The role of the ultrasound dopplerography in diagnosis of vascular diseases

European Journal of Ultrasound ◽

10.1016/s0929-8266(97)80295-9 ◽

1998 ◽

Vol 7 ◽

pp. S49

Author(s):

M.V. Isaeva ◽

M.I. Pylkov ◽

A.R. Zubarev ◽

A.V. Bystrov ◽

O.Y. Izotova ◽

...

Keyword(s):

Vascular Diseases

Download Full-text

Role of cGMP in relaxation of vascular and other smooth muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-042 ◽

1989 ◽

Vol 67 (4) ◽

pp. 251-262 ◽

Cited By ~ 43

Author(s):

Kanji Nakatsu ◽

Jack Diamond

Keyword(s):

Smooth Muscle ◽

Muscle Relaxation ◽

Smooth Muscles ◽

Phosphodiesterase Inhibitors ◽

Current Evidence ◽

Smooth Muscle Relaxation ◽

Drug Induced ◽

Intracellular Cgmp ◽

Tissue Content

The hypothesis that the relaxant action of many drugs on vascular and other smooth muscle is mediated by increases in intracellular cGMP, the "cGMP hypothesis," is gaining wide acceptance. While much information supporting this idea can be found in the literature, there is also a significant amount of information indicating that an elevation in the tissue content of cGMP is by itself insufficient to cause smooth muscle relaxation. The literature is reviewed with reference to the criteria that need to be fulfilled to consider cGMP as the second messenger mediating relaxation of smooth muscle by a drug; i.e., activation of guanylate cyclase, elevation of tissue content of cGMP, potentiation by phosphodiesterase inhibitors, antagonism by inhibitors of cGMP synthesis, and production of relaxation by cGMP analogues. For each criterion, key observations supporting the hypothesis are considered, followed by examples of important observations not consistent with the hypothesis. It is concluded that in some smooth muscles, for example, rat myometrium and vas deferens, cGMP is not a mediator of drug-induced relaxation. In other smooth muscles, including vascular smooth muscle, cGMP appears to play an important role in the relaxation process; but current evidence suggests that other factors are also important and that the cGMP hypothesis may need to be modified.Key words: cGMP, vascular relaxation, smooth muscle relaxation, vasodilators.

Download Full-text