Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.

Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo, and HF following experimental myocardial infarction (MI) in vivoMethods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca2+-regulatory genes, and induced hypertrophy without significant differences in Ca2+ transients or diastolic Ca2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF.Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF.

Region-specific patterns of vascular remodelling occur early in atherosclerosis and without loss of smooth muscle cell markers.

BACKGROUND: Vascular remodelling is characterized by increased smooth muscle cell (SMC) proliferation and migration. Coincident with these events, SMC markers of differentiation are known to down-regulate in advanced stages of atherosclerosis, a process known as phenotypic modulation. However, it is not known when this first begins. Here we sought to determine if regions of the mouse aorta with varying susceptibilities for atherosclerosis display differential vascular remodelling and SMC gene expression at the earliest stages of disease. METHODS AND RESULTS: LDLrKO mice were fed normal or high cholesterol diet for 0-98 days. In the latter, ORO and H&E staining of arch, thoracic and abdominal aortic sections revealed infrequent occurrences of lipid deposition at d28, but significant region-specific vascular remodelling. Immunostaining for PCNA revealed increased cellular proliferation in the intima and inner media at d28 in all three regions. qRT-PCR of SMC revealed increased expression of SM22alpha and SM-MHC in the arch by d28, which subsequently decreased by d98. By contrast, eNOS gene expression was consistently decreased in the arch over these times. A temporal increase in macrophage-specific CD68 expression was observed in the arch but not thoracic or abdominal regions. CONCLUSION: Remodelling of the vascular myocyte compartment due to cellular proliferation is an early event in atherosclerosis and is associated with increases in SMC-specific gene expression. These events precede subsequent lesion formation and SMC phenotypic modulation.