ABSTRACT
Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young's Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key 'linker' sites in this schema that may represent potential therapeutic targets.
Subject(s)
Cardiomyopathy, Hypertrophic , Mice , Humans , Animals , Feedback , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/metabolism , Cytoskeleton/metabolism , Myocytes, Cardiac/metabolism , Troponin I/genetics , Troponin I/metabolism , Extracellular Matrix/metabolism , HydrogelsABSTRACT
Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy characterized by left ventricular hypertrophy ≥15â¯mm in the absence of loading conditions. HCM has a prevalence of up to one in 200, and can result in significant adverse outcomes including heart failure and sudden cardiac death. An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells obtained from the whole blood of a 38-year-old female patient with HCM in which genetic testing identified the well-known pathogenic p.Arg403Gln mutation in myosin heavy chain 7. iPSCs express pluripotency markers, demonstrate trilineage differentiation capacity, and display a normal 46,XX female karyotype. This resource will allow further assessment of the pathophysiological development of HCM.
Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Induced Pluripotent Stem Cells/metabolism , Myosin Heavy Chains/genetics , Adult , Cell Differentiation , Female , Humans , MutationABSTRACT
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