113 Molecular and Cellular Biochemistry 253: 113–123, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. Molecular mechanisms in endothelial regulation of cardiac function Leena Kuruvilla and Chandrasekharan Cheranellore Kartha Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India Abstract Endothelium is now recognized as a massive, regionally specific, multifunctional organ. Given its strategic anatomic location between the circulating blood components and the vascular smooth muscle or the cardiac muscle, it is a biologically signifi- cant interface whose dysfunction can be a critical factor in various pathological conditions. Two types of endothelial cells are recognized in the heart, the endocardial endothelial (EE) cells and the microvascular endothelial cells (MVE). Both produce common autacoids and share similar roles in signal transduction induced by neurotransmitters, hormones or mechanical stimuli. They are however two distinct cell populations with dissimilar embryological origin, cytoskeletal organization, receptor me- diated functions and electrophysiological properties. Both the MVE and EE are modulators of cardiac performance. Myocar- dial contraction may be modulated by cardioactive agents such as nitric oxide, prostanoids, endothelin, natriuretic peptides, angiotensin II, kinins, reactive oxygen species and adenyl purines released from the cardiac endothelium. Two mechanisms have been proposed for the signal transduction from EE to the underlying myocytes: stimulus-secretion-contraction coupling and blood-heart barrier. Nitric oxide, bradykinin and myofilament desensitizing agent are probably important in short-term regulation of myocardial functions. Endothelin and Angiotensin II are probably involved in long-term regulation. Besides its sensory function and paracrine modulation of myocardial performance, EE as a blood-heart barrier could be of significance for the ionic homeostasis of the cardiac interstitium. In cardiac diseases, the damage to EE or MVE leading to failure of the endothelial cells to perform its regulatory and modulator functions may have serious consequences. A better understanding of the endothelial signaling pathways in cardiac physiology and pathophysiology may lead to the development of novel thera- peutic strategies. (Mol Cell Biochem 253: 113–123, 2003) Key words: heart, endocardium, myocardium, endothelium, molecular physiology, signal transduction Introduction The entire circulatory system is lined by a continuous single- cell-thick membrane – the endothelium. They form a delicate innermost monolayer of cells, lining the cavity of the heart and the luminal surface of blood vessels, the total area close to several thousand square meters. Endothelium considered for a long time as ‘a layer of nucleated cellophane’ of the blood vessel, with no major functional properties, is now rec- ognized as a massive, regionally specific, multifunctional organ [1]. This is the structure which is most exposed to me- chanical forces exerted by the blood and the substances therein. Given the strategic anatomic location of the endothe- lium between the circulating blood components and the vas- cular smooth muscle or the cardiac muscle, it is a biologically significant interface whose dysfunction can be a critical fac- tor in various pathological conditions. Each endothelial cell has a luminal surface, which faces the blood stream and an abluminal surface, which is in contact with the subendothe- lial connective tissues. These cells have high plasticity and are capable of transforming their shape and cell membrane structure as well as altering their functions and patterns of secretion of substances in response to physical and humoral stimuli [2]. Interestingly, most of the endothelium remains Address for offprints: Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India (E-mail: cckartha@sctimst.ker.nic.in)