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Heat changes the configuration and function of left ventricular (LV) in response to myocardial injury or pressure overload, which is called LV remodeling and is a major cause of heart failure. Wall stress of heart induced by pressure overload activates neurohumoral factors such as Angiotensin II, phenylephrine (PE), endothelin-1 (ET-1) known as G-protein-coupled receptor (GPCR) agonists, and cytokine (TNF-α) in the early stages. These factors bind to the receptors of cardiomyocytes and activate the intracellular signaling pathway to induce LV hypertrophy. This response is an adaptation for stress, but continuous and excessive stress breaks the compensatory mechanism, leading to cytoskeletal abnormality, apoptosis/ necrosis of cardiomyocytes and fibrosis and resulting in cardiac dysfunction and the subsequent development of heart failure. To improve prognosis in heart failure after cardiac remodeling, it is necessary to elucidate the cellular and molecular mechanism underlying the progression of cardiac remodeling.

Reactive oxygen species (ROS) is known to act as an intracellular signaling mediator. In addition, ROS induce the activation of apoptosis signal-regulating kinase 1 (ASK1) through the dissociation of thioredoxin from ASK1. ASK1 activates the c-Jun N-terminal kinase (JNK) and p38 mitogen ・activated protein (MAP) kinase, which have been known to play important roles in cardiomyocyte hypertrophy. On the basis of the evidence, we first revealed that GPCR agonists induced ROS generation in rat neonatal cardiomyocytes and furthermore that ROS-dependent signal transduction through ASK1 activation is involved in cardiomyocyte hypertrophy induced by GPCR agonists. To confirm whether ROS acts as an important signal mediator in cardiac hypertrophy in vivo, we examined the effect of the antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) on LV remodeling induced by pressure overload using the transverse thoracic aorta constriction (TAC) technique. TAC model can induce pressure overload in LV, resulting in cardiac hypertrophy without any signs of heart failure when the operated hearts are assessed 1week after TAC. Therefore this model is widely used in the study of mice to identify molecular mechanisms for cardiac hypertrophy. We should that the antioxidant edaravone significantly attenuated pressure overload-induced LV hypertrophy mediated through its antioxidant function and subsequent ASK1 inhibition. Therefore we believed that ASK1 might play a role for cardiac hypertrophy induced by pressure overload.

It has been reported that apoptosis is activated in hearts after experimental pressure overload for the long term. In heart failure after pressure-overload induced cardiac hypertrophy, cardiac myocyte apoptosis is proposed to be a critical point in the transition between compensatory hypertrophy and heart failure. Therefore, we examined to elucidate a role of ASK1 in TAC-induced LV remodeling by analyzing ASK1 knockout (KO) mice. Left ventricular and functional remodeling were determined 1 week or 4 weeks after TAC. Surprisingly, ASK KO subjected to TAC exhibited no significant difference in cardiac hypertrophy compared with wild type. These data showed that ASK1 did not play an essential role in the regulation of caridomyocyte hypertrophy in this experimental model. However, ASK KO mice had significantly attenuated LV remodeling compared to wild type mice 4 weeks after TAC. In addition, ASK KO hearts showed the remarkable decrease of TAC-induced apoptosis in cardiomyocytes compared to wild type heart. Thus, ASK1 plays an important role in regulating LV remodeling by promoting apoptosis.