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Low-Dose Aspirin Treatment Attenuates Male Rat Salt-Sensitive Hypertension via Platelet Cyclooxygenase 1 and Complement Cascade Pathway.

ABSTRACT: Background The role of platelets in the development of vascular inflammation and endothelial dysfunction in the pathogenesis of hypertension is well established at this time. Aspirin is known to relieve pain, decrease fever, reduce inflammation, impair platelet aggregation, and prevent clotting, yet its effect in the context of salt-sensitive hypertension remains unclear. The present study investigated the importance of aspirin in inhibiting the abnormal activation of platelets and promoting the normal function of the vascular endothelium in a rat model of salt-sensitive hypertension. Method and Results Dahl salt-sensitive rats and salt-resistant rats were fed a normal-salt diet (4% NaCl), a high-salt diet (8% NaCl), or a high-salt diet with aspirin gavage (10 mg/kg per day) for 8 weeks. Blood pressure, platelet activation, vascular function, inflammatory response, and potential mechanism were measured. Low-dose aspirin (10 mg/kg per day) decreased the high-salt diet-induced elevation of blood pressure, platelet activation, leukocyte infiltration, and leukocyte-platelet aggregation (CD45+CD61+), as well as vascular endothelial and renal damage. These effects were related to the ability of aspirin to prevent the adhesion of leukocytes to endothelial cells via inhibition of the platelet cyclooxygenase 1 but not the cyclooxygenase 2 pathway. Aspirin also reversed the high-salt diet-induced abnormal activation of complement and coagulation cascades in platelets. Conclusions These results highlight a new property of aspirin in ameliorating vascular endothelial dysfunction induced by platelet activation, which may be beneficial in the treatment of salt-sensitive hypertension.

SUBMITTER: Jiang X

PROVIDER: S-EPMC6988172 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Low-Dose Aspirin Treatment Attenuates Male Rat Salt-Sensitive Hypertension via Platelet Cyclooxygenase 1 and Complement Cascade Pathway.

Jiang Xiaoliang X Liu Xue X Liu Xing X Wu Xianxian X Jose Pedro A PA Liu Min M Yang Zhiwei Z

Journal of the American Heart Association 20191219 1

Background The role of platelets in the development of vascular inflammation and endothelial dysfunction in the pathogenesis of hypertension is well established at this time. Aspirin is known to relieve pain, decrease fever, reduce inflammation, impair platelet aggregation, and prevent clotting, yet its effect in the context of salt-sensitive hypertension remains unclear. The present study investigated the importance of aspirin in inhibiting the abnormal activation of platelets and promoting the ...[more]

PMID: 31852420

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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

Dataset Information

Low-Dose Aspirin Treatment Attenuates Male Rat Salt-Sensitive Hypertension via Platelet Cyclooxygenase 1 and Complement Cascade Pathway.

Publications

Low-Dose Aspirin Treatment Attenuates Male Rat Salt-Sensitive Hypertension via Platelet Cyclooxygenase 1 and Complement Cascade Pathway.

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