Old and new tools to dissect calcineurin's role in pressure-overload cardiac hypertrophy.
In the last several years, a number of experiments have implicated a pivotal role of the calcium/calmodulin-calcineurin dependent pathway as a final common signaling mechanism by which diverse hypertrophic stimuli converge to mediate hypertrophic responses in cardiomyocytes. Calcineurin inhibitors, i.e. cyclosporine A (CsA) and FK506, can interrupt the pathway, thereby preventing cardiac hypertrophy. The data that convincingly support this novel hypothesis were derived either from in vitro studies in cultured cardiomyocytes or from in vivo studies in transgenic mice. However, when the hypothesis was tested in clinically relevant animal models of cardiac hypertrophy, controversial results and conclusions emerged. In conventional models of cardiac hypertrophy, two questions remain to be answered: (1) whether calcineurin is activated in hypertrophied cardiac muscle, and (2) whether calcineurin inhibitors prevent cardiac hypertrophy. In addition, clinical observations have revealed that calcineurin inhibitors appear to exert pro-hypertrophic effects in organ transplant recipients. The controversies suggest that current calcineurin inhibitors are blunt tools for testing the hypothesis in pressure-overload hypertrophy in vivo, because there are so many confounding effects that are associated with systemic administration of the drugs. As such, new genetic approaches may overcome some of the problems associated with pharmacological inhibitors. This invited review will focus on the controversies surrounding the ability of calcineurin inhibition to prevent conventional (pressure-overload) cardiac hypertrophy and the new genetic approaches to address the question.
Zhang
Weiguo
W
Department of Internal Medicine/Hypertension Division, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8586, USA. wzhang@mednet.swmed.edu
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000318:Adrenergic beta-Agonists; D000818:Animals; D030801:Animals, Genetically Modified; D001835:Body Weight / Q000187:drug effects; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000235:genetics; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D004268:DNA-Binding Proteins; D015444:Exercise / Q000502:physiology; D018014:Gene Transfer Techniques; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D051379:Mice; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics; D051381:Rats; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use
D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000318:Adrenergic beta-Agonists; C415703:Akap5 protein, rat; C491861:CABIN1 protein, human; C113151:Cabin1 protein, mouse; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C108612:RCAN1 protein, human; D016572:Cyclosporine; D019703:Calcineurin; D007545:Isoproterenol; D016559:Tacrolimus