The Gordon Wilson Lecture: neurohormonal signaling pathways that link cardiac growth and death.
Far from being a simple muscular pump, the heart senses changes in hemodynamic forces and neurohormonal signaling, and responds by elaborating autocrine and paracrine factors that self-regulate cardiomyocyte contraction, growth, and programmed death. Interference with the afferent or efferent arms of this stress-response mechanism, as with inhibition of the beta-adrenergic or renin/angiotensin systems, is a mainstay of pharmacological therapy for heart failure. However, despite striking group-mean effects showing mortality benefits of neurohormonal antagonists, inter-individual variability in the therapeutic response to these agents suggests a pharmacogenomic interaction, where common sequence variations of genes that regulate neurohormonal signaling modify the individual response to treatment. Furthermore, there is increasing evidence that, depending upon physiological milieu, conventional neurohormone receptor-ligand pairs can activate non-traditional signaling pathways, with pathological consequences. Recently, studies that integrate the findings from human gene polymorphism discovery, recombinant gene variant expression in cell and animal models, and outcome or risk analysis of polymorphisms in human disease have provided additional understanding into adaptive and maladaptive events that are the consequence of the cardiac stress-response sequence.
Center for Molecular Cardiovascular Research, University of Cincinnati, Cincinnati, Ohio, USA. dorngw@ucmail.uc.edu
Gerald W
GW
Dorn
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016045:Human Genome Project; D006801:Humans; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D011941:Receptors, Adrenergic / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
D018377:Neurotransmitter Agents; D011941:Receptors, Adrenergic