Protein Kinase G I and Heart Failure

Abstract

In summary, basic and clinical investigations have identified multiple steps of the PKGI activation pathway that inhibit cardiac hypertrophy and remodeling and that can be targeted in the treatment of CHF. The shared property of PDE5 inhibitors, NO donors, GC activators, and neprilysin inhibitors is their cGMP-increasing effects, which activate PKGI. The rapid development of pharmacological therapies targeting this pathway has been influenced by basic science discoveries. These basic advances have also influenced the clinical scenarios in which PKGI activators are used. Although earlier trials of these agents focused predominantly on their acute hemodynamic effects, the field has begun to explore these agents as potential direct antiremodeling therapies independent of their afterload reducing effects. Ironically, although these agents initially came to clinical attention as vasodilators, it is precisely these vascular effects that, when excessive, have limited the utility of the agents as chronic therapies for patients with heart failure. PKGI has now been identified as functioning in the myocardium to inhibit cardiac remodeling. This supports future investigations to understand the currently unknown PKGI effectors expressed specifically in the myocardium and the CM. Identification of PKGI downstream antiremodeling substrates in the myocardium may identify novel therapeutic targets for chronic CHF.