SPOTLIGHT Critical review known regarding whether the stretch sensor/activator represents a defined function of a new class of stretch receptors or stretch-activated channels, or a macromolecular complex within the intracellular cytoskeleton, or perhaps a complex of ECM components. The double peak of early stretch activation responses implicates the presence of negative regulators that act as a negative feedback loop to prevent the continuous activation of any single pathway. Studies in transgenic mice now clearly document that the sustained activation of almost any individual signaling molecule may cause deleterious effects on cardiac function and promote secondary hypertrophy. Accordingly, there must be negative regulators of the response that attenuate the signal so that an orderly compensatory hypertrophic response ensues, rather than unbridled cardiac enlargement. Although numerous studies have suggested essential roles for a variety of intracellular signaling pathways in the regulation of cardiac hypertrophy and failure (1, 7), a growing number of studies have identified negative feedback regulation of these intracellular signaling pathways. In this regard, suppressor of cytokine signaling 3 (SOCS3) provides an example of a biomechanical stress–inducible negative regulator that inhibits the gp130 stress-inducible pathway for myocyte survival (5).

Within minutes of aortic constriction, gp130 ligands such as cardiotrophin-1 and leukemia inhibitory factor activate JAKs, leading to the phosphorylation of STAT3. STAT3 translocates into the nucleus and directly activates the expression of BCL-XL and VEGF and other factors that regulate myocyte survival and cardiac remodeling (8). Among these, SOCS3 is induced in the myocardium within 1 hour of aortic banding and peaks after a couple of hours. By inhibiting JAKs, SOCS3 negatively regulates stress-inducible gp130 activation. In this manner, the delicate balance between the activation of gp130-JAK signaling and the induction of its negative feedback regulator SOCS3 might be important in the transition between cardiac hypertrophy and failure, via attenuation of myocyte survival signals. Disrupting the balance between this positive and negative regulatory loop might lead to secondary effects that impair cardiac function. Accordingly, to promote gp130 myocyte survival pathways, it might be helpful to design inhibitors of the negative regulator, as opposed to designing ways to constitutively activate gp130 pathways, an event that may excessively stimulate downstream signalings. Cardiac-specific inducible mutagenesis of SOCS3 within a specific temporal period following in vivo pressure overload should be informative with regard to the validity of this new therapeutic strategy.