Significance: Calpains (CAPNs) are a family of calcium-activated cysteine proteases. The ubiquitous isoforms CAPN1 and CAPN2 have been involved in the maintenance of vascular integrity, but uncontrolled CAPN activation plays a role in the pathogenesis of vascular diseases. Recent Advances: It is well accepted that chronic and acute overproduction of reactive oxygen species (ROS) is associated with the development of vascular diseases. There is increasing evidence that ROS can also affect the CAPN activity, suggesting CAPN as a potential link between oxidative stress and vascular disease.
Critical issues: The physiopathological relevance of ROS in regulating the CAPN activity is not fully understood but seems to involve direct effects on CAPNs, redox modifications of CAPN substrates, as well as indirect effect on CAPNs via changes in Ca2+ levels. Finally, CAPNs can also stimulate ROS production; however, data showing in which context ROS are the causes or the consequences of CAPN activation are missing.
Future directions: Detailed characterization of the molecular mechanisms underlying the regulation of the different members of the CAPN system by specific ROS would help understanding the pathophysiological role of CAPN in the modulation of the vascular function. Moreover, given that CAPNs have been found in different cellular compartments such as mitochondria and nucleus as well as in the extracellular space, identification of new CAPN targets as well as their functional consequences would add new insights in the function of these enigmatic proteases.
Keywords: ROS; calpain; oxidative stress; proteolysis; vascular cells.