TY - JOUR
T1 - Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness
AU - Aroor, Annayya R.
AU - Mummidi, Srinivas
AU - Lopez-Alvarenga, Juan Carlos
AU - Das, Nitin
AU - Habibi, Javad
AU - Jia, Guanghong
AU - Lastra, Guido
AU - Chandrasekar, Bysani
AU - DeMarco, Vincent G.
N1 - Funding Information:
This research was supported by an investigator-initiated Grant from Novartis and by the Harry S. Truman VA Medical Research Foundation, Columbia, MO to VGD (LCZ696BUSNC12T). BC is a Research Career Scientist (IK6BX004016) and his work is supported by the VA ORD-BLRD Service Award I01-BX004220. Work in SM’s laboratory is supported by NIH/NIAID R01AI119131. Work in GL’s laboratory is supported by the Department of Veterans Affairs Merit System (2I01BX001981-05A1). Work in GJ’s laboratory is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK124329).
Funding Information:
Technical assistance was provided by Dongqing Chen, Brady Barron, Mona Katcher, Matt Martin, Sherrie Neff and Justin Wilson. We also appreciate the assistance provided by the Small Animal Ultrasound Imaging Center (SAUIC), located at the Harry S Truman Veterans Memorial Hospital, Columbia, MO, as well as the VA Research and Development Office and the Missouri Foundation for Veteran?s Medical Research. We also thank the Clinical Pathology Laboratory at the University of Missouri, School of Veterinary Medicine, for performing plasma and urine assays.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Objective: Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods: Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.
AB - Objective: Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods: Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results: Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions: These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.
KW - Diabetes
KW - Diastolic dysfunction
KW - Neprilysin inhibition
KW - Obesity
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U2 - 10.1186/s12933-021-01270-1
DO - 10.1186/s12933-021-01270-1
M3 - Article
C2 - 33882908
AN - SCOPUS:85104632362
VL - 20
JO - Cardiovascular Diabetology
JF - Cardiovascular Diabetology
SN - 1475-2840
IS - 1
M1 - 80
ER -