Abstract 13136: Molecular Basis of Hypothyroid Cardiomyopathy: Contrasting Changes Between Cardiac β1-Adrenergic Receptors, SERCA2a and Inducible Nitric Oxide Synthase
Background: Recent studies link hypothyroidism (Hypo) to the pathology of cardiomyopathy and heart failure. We have shown previously that Hypo is associated with defects in left ventricular (LV) myocyte force-generating capacity and relaxation with impaired [Ca2+]i regulation. However the molecular basis is unclear. We hypothesized that downregulation of LV myocyte β1-adrenergic receptors (AR) and SERCA2a, but increased inducible NOS (iNOS) are important contributing causes for the intrinsic defects of cardiomyocytes in Hypo.
Methods: Myocyte function and the expression and activity of myocyte β1- and β3-AR, SERCA2a and three nitric oxide synthases (NOS) were simultaneously evaluated in male rats of 8 Hypo (induced by 0.04% methimazole in drinking water for 8 weeks) and 8 normal controls.
Results: Compared with controls, in Hypo, total serum T4 (0.9 vs 4.2 μg/dl) and T3 (22.3 vs 88.8 ng/dl) were significantly reduced followed by significant decreases in ejection fraction (38% vs 56%) and LV contractility (EES) (0.64 vs 1.04 mmHg/μl) with increased LV time constant of relaxation (τ, 21.9 vs 11.6 ms). These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax, 59.5 vs 136.2 μm/sec), relaxation (dR/dtmax, 46.0 vs 110.1 μm/sec) and [Ca2+]iT (0.19 vs 0.26). In Hypo, isoproterenol (10-8 M) produced significantly less percent increases in dL/dtmax (31% vs 71%), dR/dtmax (30% vs 50%) and [Ca2+]iT (16% vs 35%). These changes were accompanied by significant decreases in myocyte protein levels of β1-AR (0.56 vs 0.79) and SERCA2a (0.25 vs 0.54) with 30% reduction in SERCA2a activity and no change in β3-AR, but significant increases in protein levels of iNOS (93%, 0.29 vs 0.15) and 23% decrease in eNOS with unaltered nNOS. Moreover, only in Hypo, pretreatment with 1400W significantly improved basal myocyte function (dL/dtmax, 83.9 μm/sec) and ISO-stimulated myocyte contraction (55%), relaxation (60%) and [Ca2+]iT (29%).
Conclusions: Hypothyroidism produces downregulation of cardiomyocyte β1-ARs and SERCA2a, but upregulation of iNOS, leading to myocyte systolic and diastolic dysfunction with impaired [Ca2+]i regulation, thus apparently preceding the development of hypothyroid cardiomyopathy.
- © 2013 by American Heart Association, Inc.