ABSTRACT
Hypoxia-induced apoptosis is an inevitable problem in cyanotic congenital heart disease. In the present study, we investigated effects of melatonin on hypoxic cardiomyocytes in vitro and in vivo, and explored its underlying mechanism. H9C2 cells were subjected to hypoxia for 48 hours. Mice were subjected to hypoxia treatment (10% O2) for 4 weeks. Cell viability was detected by the cell counting kit-8 assay. Cellular apoptosis was assessed by Annexin V/7 AAD assay. Western blotting was employed to determine the expression of Bcl-2, Bax, cleaved caspase 3, phosphorylation of PI3K, and AKT. Melatonin increased cell viability and alleviated apoptosis in hypoxic H9C2 cells and cardiomyocytes of hypoxia-treated mice. Melatonin pretreatment increased Bcl-2 and decreased cleaved caspase 3 and Bax levels. Moreover, melatonin activated the PI3K/Akt pathway. The protective effects of melatonin were abolished by a PI3K/Akt-inhibitor, LY294002. Our results demonstrated that melatonin confers cardioprotection by inhibiting apoptosis through the activation of PI3K/Akt signaling pathway in hypoxic cardiomyocytes.
ABSTRACT
Induction of cardiomyocyte proliferation, the most promising approach to reverse myocardial attrition, has been gaining importance as a therapy for cardiovascular disease. Hypoxia and macrophages were previously independently reported to promote cardiomyocyte proliferation in mice. However, whether hypoxia promotes cardiomyocyte proliferation in humans, and the association between hypoxia and macrophages in cardiomyocyte proliferation, have not to the best of our knowledge been previously investigated. The present study investigated the cardiomyocyte proliferation in 22 acyanotic and 29 cyanotic patients. Cardiomyocyte proliferation in a hypoxic mouse model (15% O2) was subsequently performed and the macrophage subsets were analyzed. A CC chemokine receptor type 2 (CCR2) inhibitor was used to increase the number of resident macrophages in order to investigate the effect of macrophages on cardiomyocyte proliferation. The results demonstrated that cardiomyocyte proliferation in the cyanotic infant group was significantly increased compared with the acyanotic infant group and the hypoxiatreated C57BL/6J neonates confirmed the hypoxiainduced cardiomyocyte proliferation. However, hypoxia did not induce the proliferation of isolated cardiomyocytes. Notably, hypoxia treatment increased the number of cardiac resident macrophages in neonate hearts. Furthermore, increasing the number of resident macrophages significantly enhanced cardiomyocyte proliferation. In conclusion, postnatal hypoxia promoted cardiomyocyte proliferation in humans and animals, and cardiac resident macrophages may be involved in this process. Therefore, this novel mechanism may provide a promising strategy for cardiovascular disease treatment.
Subject(s)
Hypoxia/metabolism , Macrophages/metabolism , Macrophages/pathology , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/metabolism , Adolescent , Adult , Animals , Animals, Newborn , Biomarkers , Cell Proliferation , Cells, Cultured , Child , Child, Preschool , Disease Models, Animal , Female , Humans , Infant , Macrophages/drug effects , Male , Mice , Myocytes, Cardiac/drug effects , Receptors, CCR2/antagonists & inhibitors , Young AdultABSTRACT
von Willebrand factor (vWF) was first identified as an adhesive glycoprotein involved in hemostasis by Zimmermann in 1971. Since then, vWF has been shown to play a vital role in platelet adhesion, platelet binding to collagen and factor VIII protection. Recent studies have implicated vWF as a regulator of angiogenesis, smooth muscle cell proliferation, tumor cell metastasis and crosstalk in the immune system. In this review, we will discuss the aspects of vWF structure that facilitate its biological effects and speculate on its newly discovered and hypothesized roles in the pathogenesis of several diseases.
