Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca 2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension

Yu-Ping Xie; Biyi Chen; Philip Sanders; Ang Guo; Yue Li; Kathy Zimmerman; Lie-Cheng Wang; Robert M Weiss; Isabella M Grumbach; Mark E Anderson; Long-Sheng Song

doi:10.1161/HYPERTENSIONAHA.111.180968

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Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca 2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension

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Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca 2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension

Yu-Ping Xie, Biyi Chen, Philip Sanders, Ang Guo, Yue Li, Kathy Zimmerman, Lie-Cheng Wang, Robert M Weiss, Isabella M Grumbach, Mark E Anderson, …

Hypertension (Dallas, Tex. 1979), Vol.59(2), pp.355-362

02/2012

DOI: 10.1161/HYPERTENSIONAHA.111.180968

PMID: 22203744

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Abstract

Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca(2+) release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca(2+) handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca(2+) handling protein and sarcoplasmic reticulum Ca(2+) release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy.

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Title: Subtitle: Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca 2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension
Creators: Yu-Ping Xie - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Biyi Chen - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Philip Sanders - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Ang Guo - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Yue Li - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Kathy Zimmerman - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Lie-Cheng Wang - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Robert M Weiss - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Isabella M Grumbach - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Mark E Anderson - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Long-Sheng Song - From the Division of Cardiovascular Medicine (Y.-P.X., B.C., P.S., A.G., Y.L., R.M.W., I.M.G., M.E.A., L.-S.S.), Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA; Department of Physiology (Y.-P.X., L.-C.W.), Anhui Medical University, Anhui, China; Department of Veterans Affairs Medical Center (K.Z., I.M.G.), Iowa City, IA
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.59(2), pp.355-362
DOI: 10.1161/HYPERTENSIONAHA.111.180968
PMID: 22203744
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Language: English
Date published: 02/2012
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094381702771

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