N?=?5/group. increase in the average diameter of the remaining caveolae in the mutant hearts. In accordance with these changes, Popdc1-null cardiomyocytes displayed impaired [Ca+2]i transients, increased vulnerability to oxidative stress and no pharmacologic preconditioning. In addition, induction of I/R injury to Langendorff-perfused hearts indicated a significantly lower functional recovery in the mutant compared with wild type hearts while their infarct size was larger. No improvement in functional recovery was observed in Popdc1-null hearts following ischemic preconditioning. The results indicate that Popdc1 is usually a caveolae-associated protein important for the preservation of caveolae structural and functional integrity and for heart protection. Introduction The Popeye domain name containing (Popdc) family comprises three highly conserved, developmentally-regulated genes, (blood vessel epicardial material), is considered to be the founding member and being the most analyzed one, represents the prototype for the entire Popdc gene family C. Popdc1 possesses an extracellular N-glycosylated amino-terminus, three transmembrane domains and an intracellular carboxyl-terminus. The highly conserved Popeye domain name, found in the intracellular segment, contains one or more homodimerization motifs and functions as cAMP binding domain name , C. Studies in epithelial cells have indicated that Popdc1 plays a role in cell-cell conversation and adhesion and that the conversation of Popdc1 molecules with one another is important for the maintenance of intercellular junctions C. Involvement of Popdc1 in the regulation and signaling of tight junction formation and function, vesicular transport and receptor cycling has been exhibited C. Hypermethylation of the promoter was observed during tumorigenesis and was correlated with the downregulation of expression Meisoindigo C and mutated has been identified in patients given birth to with Fallot’s tetralogy , suggesting a potential role for in the control of cell growth and differentiation and in heart morphogenesis. While expression in muscles is usually several-fold higher than in epithelia , our knowledge of function and regulation in the heart and skeletal muscle tissue is rather poor. We recognized a marked reduction in expression in end stage failing human hearts . In addition, and the other family members to bind cAMP and to interact with ion channels such as TREK-1 , . Caveolae are cholesterol and glycosphingolipid-rich plasma membrane microdomains that contain the scaffolding protein caveolin and appear as 50C100 nm plasma membrane invaginations. The caveolae serve as dynamic docking sites to organize, traffic and regulate membrane and membrane-associated signaling complexes , . The muscle mass specific caveolin3 (Cav3) and the caveolae have been found critical for cardioprotection and for ischemic preconditioning  and play a role in the modulation of calcium handling during excitation-contraction coupling and in hypertrophy C. Cav3 appears in the cardiomyocyte sarcolemma, intercalated discs and T-tubules and was recognized in the costameres, rib-like perisarcolemmal multiprotein complexes that align with Z disks and T-tubules and function in cell adhesion, stretch-sensing and pressure transmission , . Sequence analysis of Popdc1 revealed a putative caveolin binding motif within the highly conserved Popeye domain name Meisoindigo , suggesting Cav3 as a Meisoindigo potential interacting protein and caveolae as a possible membrane site for Popdc1. Given that Popdc1 is an abundant membrane Sh3pxd2a protein in cardiac myocytes, we hypothesized that Popdc1 might reside in the caveolae and function in cardiac injury and protection. We statement herein that Popdc1 is usually a caveolae-associated protein important for the maintenance of Meisoindigo caveolae number and size. Accordingly, cardiomyocytes of the mutant hearts display impaired [Ca+2]i transients, higher sensitivity to oxidative stress and no pharmacologic preconditioning while the mutant hearts are more vulnerable to I/R injury and show no ischemic preconditioning. Methods Animals Ethics Statement The study was carried out in strict accordance with the recommendations in the Guideline for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee around the Ethics of Animal Care and Use of Tel-Aviv University or college (Permits number M- 05-068 and M-09-012). Surgery was performed under isoflurane anesthesia and all efforts were made to minimize suffering. Wild type (WT) and and the related caveolae impairment will increase the heart vulnerability to nerve-racking conditions such as I/R injury and will.