Knockout of M-LP/Mpv17L, a newly identified atypical PDE, induces physiological afferent cardiac hypertrophy in mice

M-LP/Mpv17L (Mpv17-like protein) is an atypical cyclic nucleotide phosphodiesterase (PDE) without the molecular structure characteristic of the PDE family. Deficiency of M-LP/Mpv17L in mice has been found to result in development of β-cell hyperplasia and improved glucose tolerance. Here, we report another phenotype observed in M-LP/Mpv17L -knockout (KO) mice: afferent cardiac hypertrophy. Although the hearts of M-LP/Mpv17L -KO mice did not differ in size from those of wild-type mice, there was marked narrowing of the left ventricular lumen and thickening of the ventricular wall. The diameter and cross-sectional area of cardiomyocytes in 8-month-old M-LP/Mpv17L -KO mice were increased 1.16-fold and 1.35-fold, respectively, relative to control mice, but showed no obvious abnormalities of cell structure, fibrosis or impaired cardiac function. In 80-day-old KO mice, the expression of hypertrophic marker genes, brain natriuretic peptide ( BNF ), actin alpha cardiac muscle 1 ( ACTC1 ) and actin alpha 1 skeletal muscle ( ACTA1 ), as well as the Wnt/β-catenin pathway target genes, lymphoid enhancer-binding factor-1 ( LEF1 ), axis inhibition protein 2 ( AXIN2 ) and transcription factor 7 ( TCF7 ), was significantly up-regulated relative to control mice, whereas fibrosis-related genes such as fibronectin 1 ( FN1 ) and connective tissue growth factor ( CTGF ) were down-regulated. Western blot analysis revealed increased phosphorylation of molecules downstream of the cAMP/PKA signaling pathway, such as β-catenin, ryanodine receptor 2 (RyR2), phospholamban (PLN) and troponin I (cTnI), as well as members of the MEK1-ERK1/2 signaling pathway, which is strongly involved in afferent cardiac hypertrophy. Taken together, these findings indicate that M-LP/Mpv17L is one of the PDEs actively functioning in the heart and that deficiency of M-LP/Mpv17L in mice promotes physiological cardiac hypertrophy.