S1PR3
Sphingosine 1-phosphate receptor 3 (S1P receptor 3) (S1P3) (Endothelial differentiation G-protein coupled receptor 3) (Sphingosine 1-phosphate receptor Edg-3) (S1P receptor Edg-3) [EDG3]
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Elderly people often suffer adverse health because of inflammation associated with poor metabolism and cardiovascular dysfunction, but these conditions present differently in men and women. We performed experiments in aged male and female mice to understand this sexual dimorphism. We focused on sphingosine 1-phosphate (S1P) signaling, which has both protective and detrimental effects on vascular and metabolic function. We examined vascular function of mesenteric (resistance) arteries from aged male and female wild-type (WT) mice compared to littermate S1P receptor 3 (S1PR3) knockouts (KO). We also measured plasma glucose, insulin, triglycerides, adiponectin, corticosterone and inflammatory cytokines. The novel results of this study are: 1) methacholine-induced vasodilation relied completely on S1PR3 in both sexes, but was dependent on nitric oxide synthase (NOS) only in arteries from aged female mice; 2) S1P-induced vasoconstriction depended solely on S1PR3 in arteries from males, but only partly in females; 3) vasoconstriction to a thromboxane mimetic was decreased by endogenous NOS activity only in arteries from females, regardless of genotype; 4) myogenic responses were lower in arteries from aged WT males compared to females and responses in arteries from KO females were lower than WT females, while the opposite was true of arteries from male mice; 5) aged male mice showed higher fasting glucose and triglycerides with lower plasma adiponectin compared to females and 6) lack of signaling through S1PR3 in females was associated with decreased plasma adiponectin and increased inflammatory mediators. This study showed that there is considerable sexual dimorphism in the vascular and metabolic responses of aged mice and that reduced signaling through S1PR3 could be one mechanism to explain these effects. These results also emphasize that different treatments for mitigating the deleterious effects on vascular health in aged males versus females should be considered.
MeSH Terms
- Age Factors
- Aging
- Animals
- Biomarkers
- Dose-Response Relationship, Drug
- Energy Metabolism
- Female
- Genotype
- Lysophospholipids
- Male
- Mesenteric Arteries
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide Synthase
- Phenotype
- Receptors, Lysosphingolipid
- Sex Characteristics
- Sex Factors
- Signal Transduction
- Sphingosine
- Sphingosine-1-Phosphate Receptors
- Vasoconstriction
- Vasoconstrictor Agents
- Vasodilation
- Vasodilator Agents
Keywords
- Adiponectin
- Inflammation
- Mesenteric arteries
- Methacholine
- Pressure myograph
Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.
MeSH Terms
- Aging
- Animals
- Bradycardia
- Drug Evaluation, Preclinical
- Drug Therapy, Combination
- Female
- Fingolimod Hydrochloride
- Immunosuppressive Agents
- Mice
- Mice, Inbred C57BL
- Telemetry
Keywords
- Adverse effect
- Aging
- Immunomodulatory treatment
- Multiple sclerosis