SLMAP3 isoform modulates cardiac gene expression and function

• Published in: PloS one 2019-04, Vol.14 (4), p.e0214669-e0214669
• Main Authors: Mlynarova, Jana, Trentin-Sonoda, Mayra, Gaisler da Silva, Fernanda, Major, Jennifer L, Salih, Maysoon, Carneiro-Ramos, Marcela S, Tuana, Balwant S
• Format: Article
• Language: English
• Subjects: Animal genetic engineering; Animals; Biology and Life Sciences; Ca2+-transporting ATPase; Calcium; Calcium transport; Cardiac muscle; Cardiac output; Cardiology; Cardiomyocytes; Cardiovascular system; Cell membranes; Diabetic retinopathy; EDTA; EKG; Electrocardiography; Female; Fetuses; Fibrosis; Gene Expression; Genes; Genomes; Health aspects; Heart; Heart - physiology; Heart function; Heart hypertrophy; Hypertrophy; Ion channels; Ion transport; Isoforms; Kinases; Male; Medicine; Medicine and Health Sciences; Membrane proteins; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myocardial Contraction - genetics; Myocardial Contraction - physiology; Myocardium; Myocardium - metabolism; Novels; Physical Sciences; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein transport; Proteins; Research and Analysis Methods; Sarcoplasmic reticulum; Signal transduction; Sodium; Sodium channels (voltage-gated); Transcription; Transgenic mice; Transport proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0214669

The sarcolemmal membrane associated proteins (SLMAPs) belong to the super family of tail anchored membrane proteins which serve diverse roles in biology including cell growth, protein trafficking and ion channel regulation. Mutations in human SLMAP have been linked to Brugada syndrome with putative deficits in trafficking of the sodium channel (Nav1.5) to the cell membrane resulting in aberrant electrical activity and heart function. Three main SLMAP isoforms (SLMAP1 (35 kDa), SLMAP2 (45 kDa), and SLMAP3 (91 kDa)) are expressed in myocardium but their precise role remains to be defined. Here we generated transgenic (Tg) mice with cardiac-specific expression of the SLMAP3 isoform during postnatal development which present with a significant decrease (20%) in fractional shortening and (11%) in cardiac output at 5 weeks of age. There was a lack of any notable cardiac remodeling (hypertrophy, fibrosis or fetal gene activation) in Tg hearts but the electrocardiogram indicated a significant increase (14%) in the PR interval and a decrease (43%) in the R amplitude. Western blot analysis indicated a selective and significant decrease (55%) in protein levels of Nav1.5 while 45% drop in its transcript levels were detectable by qRT-PCR. Significant decreases in the protein and transcript levels of the calcium transport system of the sarcoplasmic reticulum (SERCA2a/PLN) were also evident in Tg hearts. These data reveal a novel role for SLMAP3 in the selective regulation of important ion transport proteins at the level of gene expression and suggest that it may be a unique target in cardiovascular function and disease.