Protein kinase cascades in the regulation of cardiac hypertrophy
Gerald W. Dorn II, Thomas Force
Gerald W. Dorn II, Thomas Force
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Protein kinase cascades in the regulation of cardiac hypertrophy

Abstract

In broad terms, there are 3 types of cardiac hypertrophy: normal growth, growth induced by physical conditioning (i.e., physiologic hypertrophy), and growth induced by pathologic stimuli. Recent evidence suggests that normal and exercise-induced cardiac growth are regulated in large part by the growth hormone/IGF axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive cardiac growth is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phospholipase C pathway, leading to an increase in cytosolic calcium and activation of PKC. Here we review recent developments in the area of these cardiotrophic kinases, highlighting the utility of animal models that are helping to identify molecular targets in the human condition.

Authors

Gerald W. Dorn II, Thomas Force

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GSK-3 as a convergence point in hypertrophic signaling. Inhibition of GS...
GSK-3 as a convergence point in hypertrophic signaling. Inhibition of GSK-3 appears to be a key element in both adaptive and maladaptive hypertrophy. Growth factors, acting via Akt; neurohormonal mediators, acting via both Akt and PKCs (particularly PKCα); β-adrenergic agonists, acting via PKA; and biomechanical stress, acting via several mechanisms, possibly involving the integrin-linked kinase (ILK) or an ILK-associated protein, all lead to the inactivation of GSK-3. Therefore, GSK-3 appears to serve as a convergence point, integrating inputs from many prohypertrophic signals. Inhibition of GSK-3 releases a number of transcription factors from tonic inhibition, and also releases eIF2B, allowing activation of the protein synthetic machinery. Thus GSK-3 affects both key components of the response, reprogramming of gene expression and activation of protein synthesis. Additional negative regulators of GSK-3 not shown include the serum and glucocorticoid–induced kinase (SGK) and, possibly, the ERK pathway target p90 ribosomal S6 kinase (RSK1).