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Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy.

ABSTRACT: Sarcomeric disarray is a hallmark of gene mutations in patients with Hypertrophic Cardiomyopathy (HCM). However, it is unknown when detrimental sarcomeric changes first occur and whether they originate in the developing embryonic heart. Furthermore, Rho Kinase (ROCK) is a serine threonine protein kinase that is critical for regulating the function of several sarcomeric proteins and therefore, our aim was to determine if disruption of ROCK signalling during the earliest stages of heart development would disrupt the integrity of sarcomeres altering heart development and function. Using a mouse model in which the function of ROCK is specifically disrupted in embryonic cardiomyocytes we demonstrate a progressive cardiomyopathy that first appeared as sarcomeric disarray during cardiogenesis. This led to abnormalities in the structure of embryonic ventricular wall and compensatory cardiomyocyte hypertrophy during foetal development. This sarcomeric disruption and hypertrophy persisted throughout adult life, triggering left ventricular concentric hypertrophy with systolic dysfunction, and re-activation of foetal gene expression and cardiac fibrosis, all typical features of HCM. Taken together, our findings establish a novel mechanism for the developmental origin of the sarcomeric phenotype of HCM and suggest that variants in the ROCK genes or disruption of ROCK signalling could, in part, contribute to its pathogenesis.

SUBMITTER: Bailey KE

PROVIDER: S-EPMC6538384 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy.

Bailey Kate E KE MacGowan Guy A GA Tual-Chalot Simon S Phillips Lauren L Mohun Timothy J TJ Henderson Deborah J DJ Arthur Helen M HM Bamforth Simon D SD Phillips Helen M HM

JCI insight 20190305

Sarcomeric disarray is a hallmark of gene mutations in patients with Hypertrophic Cardiomyopathy (HCM). However, it is unknown when detrimental sarcomeric changes first occur and whether they originate in the developing embryonic heart. Furthermore, Rho Kinase (ROCK) is a serine threonine protein kinase that is critical for regulating the function of several sarcomeric proteins and therefore, our aim was to determine if disruption of ROCK signalling during the earliest stages of heart developmen ...[more]

PMID: 30835717

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Project description:RATIONALE:High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE:To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS:Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. CONCLUSIONS:High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

Project description:Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and ?-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.Methods: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p?=?0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p?=?0.085). Laboratory analyses revealed normal levels of creatinine (85.5?±?18.3 vs. 81.3?±?16.4 µmol/l; p?=?0.487) and blood urea nitrogen (10.2?±?15.6 vs. 6.9?±?3.9 mmol/l; p?=?0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p?=?0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p?=?0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p?=?0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8?±?3.3, MYH7 13.9?±?6.9, p?=?0.079).Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

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Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy.

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Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy.

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