A friend within the heart: natriuretic peptide receptor signaling.

leading cause of death throughout the industrialized nations of the world. Central to this statistic is our current inability to effectively repair or otherwise reverse severe forms of cardiac dysfunction and pathologic remodeling that characterizes a failing heart. In response to hypertension, ischemic disease, valvular insufficiency, viral myocarditis, and genetic mutations in sacomeric proteins, the myocardium undergoes a hypertrophic growth phase as a compensatory measure aimed at maintaining cardiac output (1). However, longstanding cardiac hypertrophy often precipitates the development of more serious complications such as sudden death, fibrotic restrictive cardiomyopathy, dilated cardiomyopathy, and overt failure (2). Given the relatively poor clinical prognosis associated with end-stage heart failure, much investigation has focused on understanding the molecular underpinnings associated with the preceding hypertrophic remodeling stage. Indeed, a number of signaling networks have been identified that directly regulate the hypertrophic growth of cardiac myocytes (3). For example, neuroendocrine factors and/or intrinsic stretch-sensitive sensors, which signal through G protein–coupled receptors, receptor tyrosine kinases, or directly to second messengers, are thought to function as the initiating stimulus for the hypertrophic response (Figure 1). These upstream events promote signal transduction through a network of kinases and phosphatases thereby coordinating an increase in gene expression, total protein production and/or accumulation, and rRNA content, thus driving the hypertrophic growth of myocytes. However, as is common to most biological response systems, a counter-regulatory network typically exists that buffers or antagonizes the forward cascade to permit selective reversal or graded responsiveness. Indeed, in this issue of the JCI, the article by Holtwick and colleagues provides definitive evidence for the existence of an antihypertrophic regulatory circuit within cardiac myocytes that functions to directly antagonize the hypertrophic growth response (4). This antihypertrophic regulatory circuit consists of the secreted atrial and B-type natriuretic peptides (ANP and BNP, respectively), and the ANP receptor guanylyl cyclase-A (GC-A).