Pulmonary Hypertension (PH) is a serious disease associated with high mortality. Pulmonary vascular remodeling is key to PH pathogenesis and this fixed component of the disease is not effectively targeted by current therapies. Phenotypic switching of resident pulmonary vascular smooth muscle cells (VSMCs) from a contractile to a synthetic/proliferative and predominantly glycolytic phenotype contributes to pulmonary vascular remodeling in PH and likely underlies poor responsiveness to vasodilators. However, VSMC phenotypic switching is a reversible process and therefore a promising area of investigation that may lead to novel therapies that will reverse established remodeling and enhance responsiveness to pulmonary vasodilators. Understanding the role of VSMC differentiation pathways in PH pathogenesis and its reversal is thus of critical importance in identifying such novel therapeutic molecular targets. Our preliminary data support that the CArG-myocardin (MyoC)-Serum Response Factor (SRF) transcriptional complex, a master regulator of VSMC differentiation, is involved in PH pathogenesis and can be therapeutically targeted. In addition, using two experimental models of PH, we discovered that a novel intervention, using induction of mild metabolic acidosis with NH4Cl treatment, leads to prevention of PH, reversal of established remodeling and improved responsiveness to pulmonary vasodilators. The primary objectives of this proposal are (i) to define the role of the CArG-myocardin-Serum Response Factor (SRF) transcriptional complex in PH pathogenesis and its reversal (ii) to examine whether induction of clinically feasible acidosis with the use of Acetazolamide will restore a functionally contractile pulmonary VSMC phenotype in experimental PH and improve pulmonary vascular responsiveness to vasodilators. Our central hypothesis is that the CArG-MyoC-SRF transcriptional complex is involved in PH pathogenesis and that acidosis reverses pathologic pulmonary vascular remodeling by restoring a functionally contractile VSMC phenotype via this pathway.
Our specific aims are: (1) To define the role of the CArG-MyoC- SRF transcriptional complex in the development and reversal of experimental PH. (2). To test the hypothesis that EA modulates pulmonary VSMC phenotype switching via the CArG-MyoC-SRF transcriptional complex. (3). To test the hypothesis that in vivo induction of clinically feasible metabolic acidoss with Acetazolamide (ACTZ) promotes a contractile pulmonary VSMC phenotype in experimental PH. Our studies are designed to identify novel molecular targets in the CArG-MyoC-SRF pathway for therapeutic interventions for PH.

Public Health Relevance

Pulmonary hypertension (PH) is a devastating disease characterized by abnormally thick, remodeled, and stiff pulmonary vessels that fail to relax with current therapies. We have experimental evidence supporting that reversal of vessel wall remodeling and restoration of normal pulmonary vessel function is achievable in preclinical models of PH via induction of systemic metabolic acidosis. The goal of our proposed studies is to perform a rigorous investigation of the molecular pathways involved in this protective effect in order to identify novel therapeutic targets and to define the efficacy of in vivo induction of clinically feasible metabolic acidosis with Acetazolamide (ACTZ) in preclinical models of PH in order to enhance the effectiveness of current therapies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL116573-01A1
Application #
8631226
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115