Rho kinase mediates right ventricular systolic dysfunction in rats with chronic neonatal pulmonary hypertension

Kiranjot Gosal; Kristyn Dunlop; Rupinder Dhaliwal; Julijana Ivanovska; Crystal Kantores; Jean-François Desjardins; Kim A Connelly; Patrick J McNamara; Amish Jain; Robert P Jankov

doi:10.1165/rcmb.2014-0201OC

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Rho kinase mediates right ventricular systolic dysfunction in rats with chronic neonatal pulmonary hypertension

Journal article

Peer reviewed

Rho kinase mediates right ventricular systolic dysfunction in rats with chronic neonatal pulmonary hypertension

Kiranjot Gosal, Kristyn Dunlop, Rupinder Dhaliwal, Julijana Ivanovska, Crystal Kantores, Jean-François Desjardins, Kim A Connelly, Patrick J McNamara, Amish Jain and Robert P Jankov

American journal of respiratory cell and molecular biology, Vol.52(6), pp.717-727

06/2015

DOI: 10.1165/rcmb.2014-0201OC

PMID: 25337652

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Abstract

Chronic neonatal pulmonary hypertension frequently culminates in right ventricular (RV) failure and death. In juvenile rats, RV systolic dysfunction secondary to chronic hypoxia is rescued by systemic treatment with a Rho kinase (ROCK) inhibitor. To explore the relationship between ROCK inhibitor-mediated decreases in pulmonary vascular resistance and pressure, RV hypertrophy, and systolic dysfunction, we compared the effects of systemically administered to inhaled (pulmonary-selective) ROCK inhibitor on RV systolic function. Rat pups were exposed to air or hypoxia (13% O2) from Postnatal Days 1 to 21 and received rescue treatment with aerosolized fasudil (200 mM) for 15 minutes three times daily or intraperitoneal Y27632 (15 mg/kg twice daily) from Days 14 to 21. Chronic hypoxia differentially increased RhoA and ROCK activity in the right, but not left, cardiac ventricle. Inhaled ROCK inhibitor normalized pulmonary vascular resistance and caused regression of RV hypertrophy and pulmonary arterial wall remodeling but did not improve RV systolic dysfunction (decreased stroke volume and tricuspid annular plane systolic excursion). Systemic, but not inhaled, ROCK inhibitor normalized up-regulated ROCK and phosphodiesterase 5 activities in the right ventricle. Treatment with sildenafil (100 mg/kg/d intraperitoneally from Days 14 to 21) improved RV systolic function. Collectively, these data indicate that pressure unloading and regressed arterial and cardiac remodeling did not lead to recovery of systolic function while right ventricular ROCK activity remained increased. Right ventricle-specific up-regulation of RhoA/ROCK activity is critical to hypoxia-mediated systolic dysfunction, in part by regulating the activity of phosphodiesterase 5.

rho-Associated Kinases - physiology

Purines - pharmacology

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives

Rats

Ventricular Dysfunction, Right - drug therapy

rhoA GTP-Binding Protein - metabolism

Hypertrophy, Right Ventricular - etiology

Hypertrophy, Right Ventricular - enzymology

Sulfonamides - pharmacology

Ventricular Dysfunction, Right - enzymology

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - administration & dosage

Piperazines - pharmacology

rho-Associated Kinases - antagonists & inhibitors

Hypertrophy, Right Ventricular - drug therapy

Sildenafil Citrate

Animals

Heart Ventricles - enzymology

Ventricular Dysfunction, Right - etiology

Vascular Resistance - drug effects

Hypertension, Pulmonary - drug therapy

Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism

Hypertension, Pulmonary - enzymology

Hypertension, Pulmonary - complications

Details

Title: Subtitle: Rho kinase mediates right ventricular systolic dysfunction in rats with chronic neonatal pulmonary hypertension
Creators: Kiranjot Gosal - 1 Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto
Kristyn Dunlop
Rupinder Dhaliwal
Julijana Ivanovska
Crystal Kantores
Jean-François Desjardins
Kim A Connelly
Patrick J McNamara
Amish Jain
Robert P Jankov
Resource Type: Journal article
Publication Details: American journal of respiratory cell and molecular biology, Vol.52(6), pp.717-727
DOI: 10.1165/rcmb.2014-0201OC
PMID: 25337652
ISSN: 1044-1549
eISSN: 1535-4989
Grant note: MOP-84290 / Canadian Institutes of Health Research
Language: English
Date published: 06/2015
Academic Unit: Stead Family Department of Pediatrics; Neonatology; Internal Medicine
Record Identifier: 9984093333202771

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