Elimination of Senescent Cells Attenuates Obesity‐Induced Increase in Sympathetic Nerve Activity

Abstract

Obesity is a major risk factor for the development of cardiovascular diseases like hypertension. It is estimated that obesity accounts for approximately 65‐78% of hypertension in adults. Accumulating evidence suggests that increase in sympathetic nerve activity (SNA) plays a crucial role in the pathophysiology of obesity‐induced hypertension. Previous studies from our lab have shown that obesity induces cellular senescence at the level of the rostral ventrolateral medulla (RVLM), which is responsible for basal and reflex control of sympathetic activity associated with cardiovascular function. Cellular senescence is a state of permanent, irreversible cell cycle arrest in proliferative cells. Senescent cells acquire senescence‐associated secretory phenotype (SASP) and secrete proinflammatory cytokines, chemokines and proteases. These SASP factors could serve as a potential source of neuroinflammation. Based on the previous studies, our hypothesis is that obesity‐induced senescence in the RVLM contributes to neuroinflammation and increases in SNA leading to the development of hypertension. To address this hypothesis, we eliminated senescent cells using a pharmacological approach (senolytic drug) and investigated its effect on sympathoexcitation and hypertension in obesity. Two‐month‐old male C57BL/6J mice were fed a high‐fat diet (HFD; 60% fat) or a chow diet (Controls; 10% fat) for 4‐6 months. After 4‐6 months of feeding, the two groups were again subdivided into two subgroups: Vehicle and a senolytic drug combination of Dasatinib+Quercetin (D+Q). So, the four different groups are Control + Vehicle, Controls + (D+Q), HFD + Vehicle, and HFD + (D+Q). Dasatinib (5 mg/kg) plus Quercetin (50 mg/kg) was prepared in a diluted solution comprising 10% ethanol, 30% polyethylene glycol 400, and 60% Phosal 50 PG. The intervention (Vehicle or D+Q) was performed for 3 consecutive days and for 2 cycles with a 2‐week interval between cycles. Hemodynamic parameters (Blood pressure & Heart rate) and SNA were analyzed by radiotelemetry. As expected, the low frequency/high frequency heart rate variability (LF/HF HRV) ratio which is an indicator of SNA was significantly higher in HFD animals, which was reversed by senolytic drug treatment with D+Q. No changes were observed in the blood pressure. These results suggest that obesity‐induced cellular senescence causes sympathoexcitation which was reversed by the removal of senescent cells using senolytics. Future studies will investigate the mechanistic role of cellular senescence at the level of RVLM in obesity‐induced sympathoexcitation.