Pulmonary hypertension results in chronic pressure overload of the right ventricle (RV), which invariably results in right ventricular hypertrophy (RVF). Right heart failure (RHF) caused by a decompensated hypertrophic response to pressure overload is the leading cause of death in patients with severe pulmonary hypertension (SPH). Despite its profound clinical consequences, however, little is known about right ventricular adaptation and failure within the context of SPH. We propose an integrated physiological, cellular, and molecular approach to identifying the determinants of RHF in animal models of pulmonary hypertension. While many animal models of pulmonary hypertension mimic some of the pulmonary vascular changes associated with the human SPH and cause RV), few result in RHF. We show that combining chronic hypoxia with VEGF receptor blockade results in RVH that progresses to contractile dysfunction and maladaptive remodeling typical of HF, while chronic hypoxia alone produces a stable RVH and no RHF. In addition, applying VEGF receptor blockade to a pure hemodynamic stress (pulmonary artery banding) worsens RV function. The RVF triggered by these manipulations is associated with decreased NO bioavailability and alterations in the cGMP/PKG-1 signaling pathway that decrease its effectiveness in suppressing hypertrophy and potentiating VEGF signaling. Reactivating cGMP/PKG-1 signaling through chronic inhibition of the cGMP-specific phosphodiesterase 5A (PDE5AI) transforms the """"""""pathological"""""""" hypertrophic response in the hypoxia/VEGFR2 blockade model to more closely match that of """"""""physiological"""""""" hypertrophy, in which the fetal cardiac gene program is suppressed and myocyte growth is limited. Based on these preliminary data, we hypothesize that the VEGF/NO/cGMP signaling axis coordinates the growth of the adult heart (hypertrophy) to produce a stable molecular and cellular response to adverse hemodynamic and/or neurohprmonal stress. Disruption of this signaling axis and the intercellular communication between cardiac myocytes and endothelial cells leads to decompensation, maladaptive remodeling, and heart failure.
Specific Aim #1 will determine whether hemodynamic stress caused by PAH coupled with VEGF receptor blockade causes the transition from adaptive RVH to RVF.
Specific Aim #2 will determine whether disruption of VEGF/NO/GMP signaling due to underlying oxidative stress contributes to the maladaptive remodeling of the right heart and the transition to RVF.
Specific Aim #3 will identify novel genetic modifiers of RVF in the setting of pulmonary hypertension using consomic rat strains as a platform for genetic analysis. An understanding of the role of VEGF/NO/cGMP pathway in RHF and the identification of QTLs that modify the extent or susceptibility to such dysfunction is a critical step in developing rationale therapies to prevent PAH-associated RVF. Project 5 will be highly integrated with Project 4, and will provide mechanistic insights into mechanisms of RV dysfunction (Project 2) and potential biomarkers for Projects 1 and 3.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL084946-03
Application #
7802256
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$406,292
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hsu, Steven; Kokkonen-Simon, Kristen M; Kirk, Jonathan A et al. (2018) Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis-Associated Versus Idiopathic Pulmonary Arterial Hypertension. Circulation 137:2360-2370
Mercurio, Valentina; Mukherjee, Monica; Tedford, Ryan J et al. (2018) Improvement in Right Ventricular Strain with Ambrisentan and Tadalafil Upfront Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 197:388-391
Mecoli, Christopher A; Shah, Ami A; Boin, Francesco et al. (2018) Vascular complications in systemic sclerosis: a prospective cohort study. Clin Rheumatol 37:2429-2437
Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen et al. (2016) Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. Circ Cardiovasc Genet 9:64-70
Gao, Li; Emond, Mary J; Louie, Tin et al. (2016) Identification of Rare Variants in ATP8B4 as a Risk Factor for Systemic Sclerosis by Whole-Exome Sequencing. Arthritis Rheumatol 68:191-200
Hassoun, Paul M; Zamanian, Roham T; Damico, Rachel et al. (2015) Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 192:1102-10
Ohyama, Yoshiaki; Ambale-Venkatesh, Bharath; Chamera, Elzbieta et al. (2015) Comparison of strain measurement from multimodality tissue tracking with strain-encoding MRI and harmonic phase MRI in pulmonary hypertension. Int J Cardiol 182:342-348
Auer, Paul L; Nalls, Mike; Meschia, James F et al. (2015) Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JAMA Neurol 72:781-8
Parker, Sarah J; Raedschelders, Koen; Van Eyk, Jennifer E (2015) Emerging proteomic technologies for elucidating context-dependent cellular signaling events: A big challenge of tiny proportions. Proteomics 15:1486-502
Damico, Rachel; Kolb, Todd M; Valera, Lidenys et al. (2015) Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 191:208-18

Showing the most recent 10 out of 108 publications