Amphiphysin II (BIN-1) in Cardiac Muscle (p 986)
Amp II protein is required for correct formation of transverse tubules in the heart, say Caldwell et al.
Transverse (t) tubules are plasma membrane invaginations that stretch across cardiomyocytes and are closely associated with sarcoplasmic reticulum (SR). This t-tubule network is required for synchronizing the release of calcium from the SR during heart muscle contraction. Indeed, loss of t-tubules is associated with heart failure. Despite their essential function, little is known about how t-tubules are generated and the mediators regulating their formation have not been identified. One candidate mediator is Amp II, which is thought to direct calcium channels to t-tubules and is decreased in heart failure, much like t-tubules themselves. Caldwell and colleagues now show that Amp II expression not only correlates with t-tubule density, but that it also participates in their formation. In large mammals, such as humans and sheep, t-tubules are less extensive in atria than ventricles, while in mice and rat atria t-tubules are almost entirely absent. Caldwell’s team showed, that Amp II expression is lower in atria than ventricles of both large and small mammals. They then showed that silencing Amp II expression in rat ventricular cells reduced t-tubule density. It also decreased the amplitude and synchronicity of calcium release in these cells. The results suggest that boosting Amp II expression might be a way to restore t-tubules and synchronize contractility in failing hearts.
Thymidine Phosphorylase and Thrombosis (p 997)
Li et al uncover a novel target protein for anti-thrombotic therapies.
Thymidine phosphorylase, TYMP, is abundant in platelets, indeed the enzyme was originally isolated from these cells. But it was also independently identified as a proangiogenic factor, and while research continued into this area, the protein’s function in platelets remained largely unstudied. The recent finding that TYMP is highly expressed in atherosclerosis and other diseases associated with a high risk of thrombosis, however, led Li and colleagues to hypothesize that TYMP might promote platelet activation and clotting. They examined thrombus formation following carotid artery injury in wild-type and TYMP-deficient mice. In all wild-type mice, vessel occlusion occurred in an average of 11 min, while in the TYMP-deficient mice less than half of the animals had blocked vessels after 30 minutes, even though platelet numbers in both types of mice were the same. Transfusion of TYMP-lacking platelets into wild-type animals also slowed thrombus formation, showing that the thrombogenic effect of TYMP was platelet-dependent. The team also found that TYMP interacts with platelet activation factors including Lyn kinase and that inhibiting this interaction pharmacologically prevented both platelet activation and clotting in mice. Together the results suggest that inhibiting TYMP activity in platelets could be a novel antithrombotic strategy.
Abi3bp Regulates Cardiac Progenitor Cells (p 1007)
Cardiac progenitors differentiate with the help of Abi3bp protein, report Hodgkinson et al.
Cardiac progenitor cells ultimately differentiate into cardiac myocytes, smooth muscle cells and endothelium, but the factors and processes driving this differentiation have not been completely identified. The progenitors share many features with mesenchymal stem cells (MSCs), leading Hodgkinson and colleagues to wonder whether the protein Abi3bp, which prompts differentiation in MSCs, might play the same role in cardiac progenitors. They observed that expression of Abi3bp was 100-fold lower in isolated cardiac progenitors than in cardiac myocytes, but that its expression was increased upon differentiation. Moreover, cardiac progenitors from Abi3bp-lacking mice failed to differentiate correctly in culture, exhibiting aberrant expression levels of cardiac myocyte differentiation markers. This impaired differentiation also correlated with impaired recovery after myocardial infarction in the Abi3bp-lacking mice. The team also found that Abi3bp interacts with integrin-β, and that this partnership, together with the downstream phosphorylation of kinases PKC and Akt, is important for Abpi3bp-driven cardiac myocyte differentiation. The finding that Abi3bp promotes cardiac progenitor differentiation and improves heart tissue recovery after injury may be important for designing future progenitor-based therapies, say the authors.
- © 2014 American Heart Association, Inc.