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α1A‐Subtype Adrenergic Agonist Therapy for Failing Right Ventricle
Author(s) -
Cowley Patrick M,
Wang Guanying,
Swigart Philip M,
Lovett David H,
Simpson Paul C,
Baker Anthony J
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.687.9
Subject(s) - medicine , heart failure , ventricle , inotrope , endocrinology , bleomycin , fibrosis , cardiac fibrosis , agonist , pulmonary fibrosis , myofilament , stimulation , cardiology , receptor , myocyte , chemotherapy
Experimental and clinical evidence suggests that signaling by α1‐adrenergic receptors (α1‐ARs) is increased in heart failure and that this increase is beneficial. In a mouse model of failing right ventricle (RV) we found that the α1‐AR inotropic (contractile) response was increased. Of the two predominant α1‐AR subtypes on cardiac myocytes (α1A and α1B), we found that the increased inotropic response was mediated solely by the α1A‐subtype. Our recent studies find that in a mouse model of RV failure, chronic stimulation of the α1A‐subtype with the selective agonist A61603 has multiple beneficial effects, including decreased necrosis, and increased myofilament force. The mechanisms for these beneficial effects are unknown. Goal Determine the mechanisms for the beneficial effects of chronic α1A‐subtype stimulation on the failing RV. Methods We used a mouse model of RV failure induced by tracheal instillation of the fibrogenic antibiotic bleomycin to cause pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Mice were treated concurrently using osmotic mini‐pump chronic infusion of a low dose of A61603 (10ng/kg/day) or saline (control). Results Compared to non‐failing RV, the bleomycin model of RV failure resulted in decreased RV fractional shortening in‐vivo, increased cardiac fibrosis, increased serum levels of cardiac TnI, and decreased contraction strength of cardiac myofilaments. These changes were abolished by chronic treatment with A61603. Compared to non‐failing RV, the bleomycin model of RV failure was associated with increased levels of the oxidative‐stress mediated protein adduct 4‐HNE (4‐Hydroxynonenal), and increased levels of the oxidant‐producing enzyme NOX‐2. These changes were abolished by chronic treatment with A61603. Moreover, chronic treatment with A61603 increased the level of the endogenous antioxidant superoxide disumutase‐1 (SOD1). Oxidative stress is known to activate transcription of matrixmetalloproteinase‐2 (MMP‐2) that can result in both extracellular and intracellular dysfunctional remodeling. Levels of MMP‐2 were increased in the bleomycin model of RV failure, and this increase was abolished by chronic treatment with A61603, which may have contributed to better preservation of myofilament integrity and force production with A61603 treatment. Summary and Conclusions Chronic treatment of failing RV with A61603 reduces oxidative stress injury, possibly by reducing oxidant production and increasing antioxidant SOD1 levels. Reduced oxidative stress due to chronic A61603 treatment may result in decreased oxidative‐stress‐activation of MMP‐2, leading to decreased dysfunctional remodeling. Stimulation of the α1A‐subtype is a novel therapy for RV failure. Support or Funding Information This work was supported by Department of Veterans Affairs Merit Review Awards I01BX000740 (AJB), I01BX001970 (PCS), National Heart, Lung and Blood Institute Grant HL31113 (PCS) and the American Heart Association (AJB)