title: Lactation Is a Risk Factor of Postpartum Heart Failure in Mice with Cardiomyocyte-specific Apelin Receptor (APJ) Overexpression.
abstract: The G protein-coupled receptor APJ and its ligand apelin are highly expressed in cardiovascular tissues and are associated with the regulation of blood pressure and cardiac function. Although accumulating evidence suggests that APJ plays a crucial role in the heart, it remains unclear whether up-regulation of APJ affects cardiac function. Here we generated cardiomyocyte-specific APJ-overexpressing (APJ-TG) mice and investigated the cardiac phenotype in APJ-TG mice. Male and non-pregnant APJ-TG mice showed cardiac hypertrophy, contractile dysfunction, and elevation of B-type natriuretic peptide gene expression in the heart but not cardiac fibrosis and symptoms of heart failure, including breathing abnormality and pleural effusion. We further examined the influence of APJ overexpression in response to physiological stress induced by pregnancy and lactation in the heart. Interestingly, repeating pregnancy and lactation (pregnancy-lactation cycle) exacerbated cardiac hypertrophy and systolic dysfunction and induced cardiac fibrosis, lung congestion, pleural effusion, and abnormal breathing in APJ-TG mice. These data indicate that female APJ-TG mice develop postpartum cardiomyopathy. We showed that lactation, but not parturition, was critical for the onset of postpartum cardiomyopathy in APJ-TG mice. Furthermore, we found that lactating APJ-TG mice showed impaired myocardial angiogenesis and imbalance of pro- and antiangiogenic gene expression in the heart. These results demonstrate that overexpression of APJ in cardiomyocytes has adverse effects on cardiac function in male and non-pregnant mice and that lactation contributes to the development of postpartum cardiomyopathy in the heart with APJ overexpression.
authors.affiliation: From the Life Science Center, Tsukuba Advanced Research Alliance, and.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Murata
authors.affiliation: From the Life Science Center, Tsukuba Advanced Research Alliance, and Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishimaru
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Hayase
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: From the Life Science Center, Tsukuba Advanced Research Alliance, and.
authors.forename: Juri
authors.initials: J
authors.lastname: Hamada
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Saito
authors.affiliation: From the Life Science Center, Tsukuba Advanced Research Alliance, and Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan akif@tara.tsukuba.ac.jp.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: D000818:Animals; D000075244:Apelin Receptors; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007774:Lactation; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010996:Pleural Effusion / Q000235:genetics / Q000473:pathology; D049590:Postpartum Period / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: APJ; G protein-coupled receptor (GPCR); cardiac hypertrophy; cardiomyopathy; heart; heart failure; lactation; pregnancy