Stretching to meet needs: integrin-linked kinase and the cardiac pump

In an elegant set of genetic and biochemical experiments reported in this issue of Genes & Development, Bendig et al. (2006) show that integrin-linked kinase (ILK) is a critical component of the cardiac stretch sensor. Their findings link the cell surface and actin cytoskeleton to central signaling pathways. Here we discuss the significance of this work in light of other recent discoveries on the molecular mechanisms of cardiac stretch sensing. The heart has the extraordinary capability of responding to physiologic demand by rapidly altering the amount of blood pumped with each heartbeat. Similarly, in response to pathologic conditions, the heart expands to increase cardiac output, although continued expansion eventually diminishes its ability to pump effectively. Widely known as the Frank-Starling curve, this property was described by Otto Frank and Ernest Henry Starling in 1918 (Fig. 1; Starling 1918). The molecular and cellular basis for rapid alteration in the contractility of heart muscle has attracted intense scientific interest focusing on the ability of the myocardium to sense “stretch” and respond by increasing strength of contraction and hypertrophy of individual myocytes. The primary function of the heart is to supply oxygenated blood to peripheral tissues to meet metabolic demands. Heart failure—the leading cause of morbidity and mortality in the industrialized countries—occurs when cardiac output cannot meet metabolic requirements (Molkentin and Dorn 2001). Although the etiology and manifestations of heart failure are varied, a common early sign is pathological hypertrophic remodeling of the left ventricle (Tarone and Lembo 2003). In cardiac hypertrophy, cardiomyocytes increase in size by adding more sarcomeres to myofibrils to normalize myocardial wall stress from hemodynamic overload. Through complex and unclear mechanisms, persistent cardiac hypertrophy often leads to decreased contractility and dilated cardiomyopathy. Cardiac hypertrophy is triggered by mechanical stretching of cardiomyocytes and release of neurohumoral factors, such as angiotensin II and epinephrine in response to pressure overload (Wakatsuki et al. 2004). Mechanical stretching also promotes the release of autocrine and paracrine factors by cardiomyocytes and fibroblasts that activate hypertrophic and contractility signaling pathways (Sadoshima and Izumo 1997; Hunter and Chien 1999; Tarone and Lembo 2003). Ultimately, these pathways lead to the expression of stretch-responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) (Pan et al. 1999; Seko et al. 1999; Franchini et al. 2000; Molkentin and Dorn 2001; Domingos et al. 2002; Kim et al. 2002; Zhang et al. 2003). Vegf transcription is stimulated by PKB/Akt and increases calcium transients that result in greater cardiac contractility (Rottbauer et al. 2005). These signaling pathways have been studied extensively by many groups in an effort to develop therapies for hypertrophic remodeling (Frey et al. 2004), but only recently have we began to understand how mechanical stretching is sensed by cardiomyocytes.