Hypertrophic cardiomyopathy (CMH) is a genetic myocardial disease characterized by left ventricular hypertrophy mainly affected the interventricular septum, diastolic dysfunction and increased interstitial fibrosis. More than 450 different mutations have been identified in genes encoding sarcomeric proteins. The two most frequently mutated genes (~80% of the families) are the MYH7, encoding the beta-myosin heavy chain (beta-MHC) and MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C).

 

The first disease MYH7 gene for familial HCM was identified in the early 90th by the team of C. Seidman (Boston). This opened the way of genetic cardiology. Quickly thereafter, genetic heterogeneity has been demonstrated by different teams. Particularly, the creation of a French Inserm network in 1992 coordinated by K. Schwartz and M. Komajda group and later a European Network coordinated by R. Isnard (Eurogene Heart Failure, Leducq Foundation 2000-2004) allowed the recruitment of more than 300 index cases with HCM and their relatives. The major discoveries were:
(1) Identification of the CMH4 locus on chromosome 11 (Carrier et al., Nature Genet 1993);
(2) Identification of the HCM disease gene MYBPC3 encoding cMyBP-C (Bonne/Carrier et al., Nature Genet 1995);
(3) Determination of the complete structure and organization of the MYBPC3 gene and demonstration that most of the mutations should produce C-terminal truncated cMyBP-C (Carrier et al., Circ Res 1997);
(4) Demonstration that MYBPC3 and MYH7 mutations are the most frequent causes of HCM in a panel of 124 unrelated families (Richard et al., Circulation 2003);
(5) Identification of a new genetic variant in the promoter of calmodulin III that contributes to the phenotype of HCM (Friedrich et al., Eur Heart J 2009).

 

This project evaluates the role of cMyBP-C in the sarcomere structure and function in both healthy and disease situations. The major findings are:

(1) Expression of cMyBP-C is restricted to the heart during human and mouse development (Fougerousse et al., Circ Res 1998);
(2) Instability of human truncated cMyBP-Cs after gene transfer in cardiomyocytes (Flavigny et al., J Mol Biol 1999);
(3) Disorganization of myosin filaments by truncated cMyBP-Cs in non-muscle cells (Sebillon et al. C R Acad Sci 2001),
(4) Absence of interaction between recombinant human truncated cMyBP-Cs and human beta-MHC in biosensor chips (Flavigny et al., Cardiovasc Res 2003);
(5) Evidence of asymmetric septal hypertrophy in heterozygous cMyBP-C null mice, which constituted the first model with the major feature of HCM (Carrier et al., Cardiovasc Res 2004);
(6) Evidence for reduced phosphorylation levels of cMyBP-C in human and experimental heart failure (El-Armouche et al., J Mol Cell Cardiol 2007);
(7) Requirement of cMyBP-C for complete relaxation in cardiomyocytes (Pohlmann et al., Circ Res 2007) ;
(8) cMyBP-C regulates the tuning of molecular motor in the heart (Lecarpentier et al., Biophys J 2008).

 

This project has started with the discovery that truncated cMyBP-Cs are unstable after gene transfer in cardiac myocytes (Flavigny et al., J Mol Biol 1999). The project evaluates the role of the ubiquitin-proteasome system (UPS) and lysosome-autophagy in the degradation of truncated cMyBP-C and investigates more generally these two systems in HCM and heart failure. The main findings were 

(1) Impairment of the UPS by truncated cMyBP-Cs after adenoviral gene transfer in cardiomyocytes (Sarikas/Carrier et al., Cardiovasc Res 2005);
(2) degradation of truncated cMyBP-C is mediated by the E3 ubiquitin ligases atrogin-1 after gene transfer in cardiomyocytes (Mearini et al., Cardiovasc Res 2010) ;
(3) regulation of the expression of a human cMyBP-C mutation in mice (knockin mice; KI) involves not only the UPS, but also the nonsense-mediated mRNA decay and an unexpected re-framing after exon skipping (Vignier/Schlossarek et al., Circ Res 2009);
(4) alterations of the UPS are part of a general cardiac hypertrophy program; however, experiments with UPS-reporter mice provided first evidence that the UPS may be specifically compromised in KI mice expressing truncated cMyBP-C, but not in those devoid of them (cMyBP-C-KO; for recent review of the team, see  Mearini et al., Biochem Biophys Acta 2008 ; Carrier et al., Cardiovasc Res 2010).

 

The current projects and perspectives evaluate new therapeutical approaches for HCM in disease mouse models. We investigate pharmacological targets (inhibition of the UPS, beta-blockers, inhibitions of calcium and sodium channels and inhibition of the sodium/proton exhanger), as well as RNA-based therapies, such as exon-skipping and spliceosome-mediated RNA transplicing.

 

 

Update: April 2010