Richard T Clements1,2,3, Alexander Vang1, Ana Fernandez-Nicolas1,4, Nouaying R Kue1, Thomas J Mancini1, Alan R Morrison1,4, Krishna Mallem1, Danielle J McCullough5, Gaurav Choudhary1,4. 1. Vascular Research Laboratory, Providence VA Medical Center, RI (R.T.C., A.V.A.B., A.F.-N., N.R.K., T.J.M., A.R.M., K.M., G.C.). 2. Department of Surgery, Warren Alpert Medical School of Brown University, Providence, RI (R.T.C.). 3. Department of Biomedical and Pharmaceutical Science, College of Pharmacy, University of Rhode Island, Kingston, RI (R.T.C.). 4. Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI (A.F.-N., A.R.M., G.C.). 5. Department of Anatomical Sciences, Edward Via College of Osteopathic Medicine-Auburn Campus, AL (D.J.M.).
Abstract
BACKGROUND: Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling. METHODS: PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON-normoxic animals with placebo (n=18); PH-Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16). RESULTS: In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone. CONCLUSIONS: Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.
BACKGROUND:Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling. METHODS:PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON-normoxic animals with placebo (n=18); PH-Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16). RESULTS: In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone. CONCLUSIONS:Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.
Authors: Harm J Bogaard; Ramesh Natarajan; Shiro Mizuno; Antonio Abbate; Philip J Chang; Vinh Q Chau; Nicholas N Hoke; Donatas Kraskauskas; Michael Kasper; Fadi N Salloum; Norbert F Voelkel Journal: Am J Respir Crit Care Med Date: 2010-05-27 Impact factor: 21.405
Authors: Michiel Alexander de Raaf; Ingrid Schalij; Jose Gomez-Arroyo; Nina Rol; Chris Happé; Frances S de Man; Anton Vonk-Noordegraaf; Nico Westerhof; Norbert F Voelkel; Harm Jan Bogaard Journal: Eur Respir J Date: 2014-05-02 Impact factor: 16.671
Authors: Abdallah Alzoubi; Michie Toba; Kohtaro Abe; Kealan D O'Neill; Petra Rocic; Karen A Fagan; Ivan F McMurtry; Masahiko Oka Journal: Am J Physiol Heart Circ Physiol Date: 2013-04-12 Impact factor: 4.733
Authors: Emily K Zern; Susan Cheng; Aaron M Wolfson; Michele A Hamilton; Michael R Zile; Scott D Solomon; Michelle M Kittleson Journal: Circ Heart Fail Date: 2020-02-14 Impact factor: 8.790
Authors: Alexander Vang; Denielli da Silva Gonçalves Bos; Ana Fernandez-Nicolas; Peng Zhang; Alan R Morrison; Thomas J Mancini; Richard T Clements; Iuliia Polina; Michael W Cypress; Bong Sook Jhun; Edward Hawrot; Ulrike Mende; Jin O-Uchi; Gaurav Choudhary Journal: JCI Insight Date: 2021-06-22