Annexins: Roles in the Regulation of Ca²⁺ Handling Proteins During Heart Failure

Abstract

Annexins are a family of 13 proteins known to bind phospholipids in a Ca²⁺-dependent way (1,2). They share a similar structure characterized by a conserved exterminai domain and a variable N-terminal domain. They are thought to participate in a variety of membrane-related events such as exocytosis, endocytosis, binding to cytoskeletal proteins but also to regulate protein activities. In the myocardium, annexin VI is the most abundant and has been localized in various cell types including myocytes. It has been involved in the regulation of Ca²⁺ handling proteins and surexpression or knockout of the annexin VI gene leads to changes in Ca²⁺ homeostasis and contractility. Expression and localization of annexin VI is either faintly or not modified during heart failure. Annexin V is mainly localized in the sarcolemma and T-tubules of cardiomyocytes and in endothelial cells. In the failing heart, expression of annexin V is increased and localization becomes heterogenous leading to myocytes devoided of annexin V and interstitial tissue strongly labelled. Annexin VII is known as a skeletal muscle annexin but is also expressed in the heart. It is the third annexin which could be related to regulation of Ca²⁺ handling proteins because the knockout of the annexin VII gene shows a decrease in the force-frequency relationship in adult cardiomyocytes. The major endothelial annexin is annexin II which is involved in membrane trafficking, collagen binding and plasminogen activation. It is absent from myocytes. During heart failure, the increase in annexin II might play a role in the extracellular matrix remodeling. From these studies, it is tempting to speculate that annexins, at least annexins V, VI and VII, might play a role in the regulation of Ca²⁺ handling proteins during heart failure.