Identification of membrane palmitoylated protein 1 (MPP1) as a heart-failure-promoting protein triggered by cardiovascular risk factors and aging

Abstract

Membrane-Associated Guanylate Kinase (MAGUK) proteins are scaffold proteins with well-established functions in the neuronal system. A role of MAGUK protein up-regulation in the pathogenesis of heart failure is not established. This study identified the up-regulation of the MAGUK family protein MPP1 (Membrane Palmitoylated Protein 1), in cardiac transcriptome data of three different heart failure models. MPP1 was up-regulated in failing hearts of B6 mice with long-term chronic pressure overload, in failing hearts of aged Apoe−/− mice with long-term atherosclerosis, and in failing hearts of RKIP-transgenic mice with cardiotoxic lipid overload. MPP1-transgenic mice revealed that moderately (2-fold) increased cardiac MPP1 levels caused symptoms of heart failure with a significantly reduced left ventricular ejection fraction of 39.0 ± 6.9 % in Tg-MPP1 mice compared to 55.2 ± 3.7 % of non-transgenic B6 controls. Echocardiographic and histological analyses detected cardiac enlargement and cardiac dilation in Tg-MPP1 mice. The angiotensin II AT1 receptor (AGTR1) and MPP1 were co-localized on sarcolemmal membranes in vivo, and Tg-MPP1 mice had increased levels of cardiac AGTR1, which has an established heart failure-promoting function. The increased AGTR1 protein could be directly triggered by elevated MPP1 because MPP1 also increased the AGTR1 protein in non-cardiomyocyte HEK cells, which was detected by fluorescence measurement of AGTR1eYFP. MPP1 was not only up-regulated by major cardiovascular risk factors but also by old age, which is a major contributor to heart failure. Thus, the aging-induced MPP1 exerts a previously unrecognized role in heart failure pathogenesis by upregulation of the angiotensin II AT1 receptor (AGTR1) protein.