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Abstract-Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the ␣-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor. Key Words: VEGF-B Ⅲ cardiac hypertrophy Ⅲ cardiac metabolism Ⅲ fatty acids Ⅲ mitochondria M embers of the vascular endothelial growth factor (VEGF) family, currently comprising 5 mammalian proteins, are major regulators of blood and lymphatic vessel development and growth. VEGF is essential for vasculogenesis and angiogenesis, whereas VEGF-C is necessary for lymphangiogenesis. Although not required for embryonic development, placenta growth factor and VEGF-D are likely to play more subtle roles in the control of angiogenesis and lymphangiogenesis, or function under pathological conditions. 1,2 VEGF-B exists as 2 isoforms generated by alternative splicing. VEGF-B 167 has a heparin-binding carboxyl terminus, whereas VEGF-B 186 contains a hydrophobic carboxyl terminus, is O-glycosylated, and proteolytically processed. 3 Both isoforms bind to VEGF receptor (VEGFR)-1 and neuropilin-1 but not to the major mitogenic endothelial cell receptors VEGFR-2 or VEGFR-3. 4,5 VEGF-B has a wide tissue distribution, being most abundant in the myocardium, skeletal and vascular smooth muscle, as well as in brown adipose tissue. 6 Mice lacking VEGF-B are viable and fertile and display only a mild phenotype in the heart. This is manifested as an atrial conduction abnormality characterized by a prolonged PQ interval in 1 strain (C57Bl background), 7 or as a smaller heart size with impaired recovery after myocardial ischemia in another (129/SvJ or 129/SvJϫC57Bl/6J background). 8 Furthermore, VEGF-B has also been implicated in pathological vascular changes in inflammatory arthritis 9 and in protecting the brain from ischemic injury. 10 H...

Apelin and its G-protein-coupled receptor APJ have various beneficial effects on cardiac function and blood pressure. The mechanisms that regulate apelin gene expression are not known. Because apelin gene expression has been shown to increase in cardiac ischemia, we investigated if apelin (Apln) gene expression was sensitive to hypoxia. Here we show that hypoxia increases the apelin expression in rat myocardium and in cultured cardiomyocytes. Pharmacological activation of hypoxia inducible factor by desferrioxamine (DFO) or expression of a constitutively active form of HIF-1alpha increased apelin expression in cardiomyocyte cultures. The induction of apelin by hypoxia was abolished on transient expression of the HIF inhibitory PAS protein in cardiomyocytes. Increased apelin expression induced by hypoxia or DFO was accompanied by the processing of the cellular storage form proapelin into smaller apelin peptides and increased secretion of these biologically active forms of apelin. In a rat in vivo model, acute myocardial infarction (24 h) led to a transient increase in ventricular apelin mRNA levels. Our results indicate that apelin gene is regulated by hypoxia in cardiac myocytes via the HIF pathway, suggesting a role for apelin as a potential marker for acute cardiac hypoxia with a possible compensatory role in myocardial tissue suffering from oxygen deprivation.

Abstract-Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38␣ in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion, and transcription. A large number of previously unknown p38 target genes were found. Using gel mobility-shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene-expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression-induced gene expression results in myocardial cell proliferation, inflammation, and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. (Circ Res. 2006;99:485-493.)