The cardiac myocyte-specific role of PKG-1 alpha in cardiac remodeling
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Abstract
Current dogma holds that the cGMP dependent protein kinase (PKG) acts in the cardiovascular system (CVS) mainly through the vascular smooth muscle cell (VSMC) to regulate blood flow and vascular tone via nitric oxide (NO) induced vasodilation. Yet, the role of PKG in the CVS, outside the VSMC, remains largely unexplored. Recent studies have revealed that PKG also functions as an anti-hypertrophic molecule in the heart, attenuating cardiac remodeling and preventing the progression of congestive heart failure (CHF). However, those studies used pharmacological agents which increased whole-body cGMP to activate PKG. One more attractive therapeutic strategy would be to activate PKG in cell-types specific to the heart, but not to the peripheral vasculature, since this might provide a more direct treatment for CHF with fewer adverse side effects. Therefore, we tested the specific hypothesis that PKG-Iα attenuates cardiac hypertrophy and remodeling in vivo through a specific role inthe cardiac myocyte (CM). Genotypically, we compared aMHC-Cre+/-, PKG-Iαfl/fl (Cre+) mice to aMHC-Cre-/-, PKG-Iαfl/fl (Cre-) control mice. Here we have shown that Cre+ mice lose the ability to inhibit cardiac remodeling in an unstressed state. Cre+ mice have increased heart weights, CM size, fibrosis, and contractile dysfunction, compared to Cre- mice. Additionally, Cre+ mice show increased fetal gene expression indicative of remodeling. Lastly, these effects worsened in an age-dependent manner. These data suggest that inhibition of cardiac remodeling occurs principally through PKG-Iα in the CM, and reveal new roles for PKG in the CVS, and as a novel target for CHF therapy.
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Thesis (M.A.)--Boston University
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