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Activation of mitogen-activated protein kinases in cardiovascular hypertrophy and remodeling
Abstract:
Extracellular signal-regulated kinases (ERKs) and c-jun NH2-terminal kinases (JNKs), which belong to the family of mitogen-activated protein kinases (MAPKs), play a key role in the regulation of cell growth or apoptosis or various gene expressions. In spite of the critical importance of MAPKs for cell function in vitro, the role of MAPKs in the pathophysiology of the cardiovascular system in vivo is poorly understood. Recently, we have examined the activities of MAPKs in various cardiovascular disease models. JNKs activity is chronically enhanced in cardiac hypertrophy of hypertensive rats or angiotensin II-infused rats, which is followed by the increase in activator protein-1 (AP-1) activity composed of c-Fos and c-Jun proteins. In chronic hypertensive rats, vascular ERKs and JNKs activities are continuously increased compared with normotensive rats, with the development of vascular thickening. Furthermore, balloon injury rapidly and transiently activates vascular ERKs and JNKs, followed by the activation of AP-1. This activation of ERKs and JNKs in injured artery is in part mediated by angiotensin AT1 receptor. Thus, the enhanced activation of JNKs or ERKs occurs in various cardiovascular disease models, supporting the notion that MAPKs may be a useful target for treatment of cardiovascular hypertrophy and remodeling.
Insights
Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and c-jun NH2-terminal kinases (JNKs), are activated in cardiovascular disease models. Enhanced MAPK activity suggests potential therapeutic targets for cardiovascular hypertrophy and remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Signaling
- Cellular Stress Response
Background:
- Mitogen-activated protein kinases (MAPKs), encompassing extracellular signal-regulated kinases (ERKs) and c-jun NH2-terminal kinases (JNKs), are crucial for cellular processes like growth and apoptosis.
- While their in vitro importance is established, the in vivo role of MAPKs in cardiovascular pathophysiology remains less understood.
Purpose of the Study:
- To investigate the activity and role of MAPKs in various cardiovascular disease models in vivo.
- To explore the relationship between MAPK activation and cardiovascular hypertrophy and vascular remodeling.
Main Methods:
- Analysis of MAPK (ERK and JNK) activities in rat models of cardiac hypertrophy and hypertension.
- Assessment of vascular MAPK activation in response to chronic hypertension and acute vascular injury (balloon angioplasty).
- Investigation of the involvement of the angiotensin AT1 receptor in mediating vascular MAPK activation.
Main Results:
- JNK activity was chronically elevated in cardiac hypertrophy models (hypertensive and angiotensin II-infused rats), correlating with increased activator protein-1 (AP-1) activity.
- Both vascular ERKs and JNKs showed sustained increases in activity in chronic hypertensive rats, coinciding with vascular thickening.
- Balloon injury induced rapid, transient activation of vascular ERKs and JNKs, partly mediated by the angiotensin AT1 receptor.
Conclusions:
- Enhanced activation of JNKs and ERKs is a common feature across different cardiovascular disease models.
- MAPKs, particularly JNKs and ERKs, represent promising therapeutic targets for mitigating cardiovascular hypertrophy and pathological remodeling.