Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 167, Issue -, Pages 32-39Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.03.006
Keywords
Obesity; Sphingomyelinases; Arterial stiffness; Hypertension; Inflammation
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [DK124329]
- American Diabetes Association Innovative Basic Science Award [1-17-IBS-201]
- NIH [RO1HL085119, R01 HL73101-01A, R01 HL107910-01]
- Veterans Affairs Merit System Grants [BX003391]
- Truman VA Medical Research Foundation
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Sphingomyelinases, especially neutral sphingomyelinase, play a crucial role in cell turnover, vesicles budding, and exosome release. In this study, the researchers found that inhibiting neutral sphingomyelinase can attenuate Western diet-induced aortic stiffness and impaired vasomotor function by reducing oxidative stress, inflammation, and adverse vascular remodeling.
Sphingomyelinases ensure ceramide production and play an integral role in cell turnover, inward budding of vesicles and outward release of exosomes. Recent data indicate a unique role for neutral sphingomyelinase (nSMase) in the control of ceramide-dependent exosome release and inflammatory pathways. Further, while inhibition of nSMase in vascular tissue attenuates the progression of atherosclerosis, little is known regarding its role on metabolic signaling and arterial vasomotor function. Accordingly, we hypothesized that nSMase inhibition with GW4869, would attenuate Western diet (WD) -induced increases in aortic stiffness through alterations in pathways which lead to oxidative stress, inflammation and vascular remodeling. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were variably treated with GW4869 (2.0 mu g/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and activation while causing aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. Moreover, these functional abnormalities were associated with aortic remodeling and attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. GW4869 treatment prevented the WD-induced increases in nSMase activation, PWV, and impaired endothelium dependent/independent vascular relaxation. GW4869 also inhibited WD-induced aortic CD36 expression, lipid accumulation, oxidative stress, inflammatory responses, as well as aortic remodeling. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and impaired vascular relaxation by attenuating oxidative stress, inflammation and adverse vascular remodeling.
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