Rescue of familial cardiomyopathies by modifications at the level of sarcomere and Ca2+ fluxes.
Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that frequently show inappropriate ventricular hypertrophy or dilation. Current data suggest that numerous mutations in several genes can cause cardiomyopathies, and the severity of their phenotypes is also influenced by modifier genes. Two major types of inherited cardiomyopathies include familial hypertrophic cardiomyopathy (FHC) and dilated cardiomyopathy (DCM). FHC typically involves increased myofilament Ca(2+) sensitivity associated with diastolic dysfunction, whereas DCM often results in decreased myofilament Ca(2+) sensitivity and systolic dysfunction. Besides alterations in myofilament Ca(2+) sensitivity, alterations in the levels of Ca(2+)-handling proteins have also been described in both diseases. Recent work in animal models has attempted to rescue FHC and DCM via modifications at the myofilament level, altering Ca(2+) homeostasis by targeting Ca(2+)-handling proteins, such as the sarcoplasmic reticulum ATPase and phospholamban, or by interfering with the products of different modifiers genes. Although attempts to rescue cardiomyopathies in animal models have shown great promise, further studies are needed to validate these strategies in order to provide more effective and specific treatments.
Alves
Marco L
ML
Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago , IL 60612, USA.
Gaffin
Robert D
RD
Wolska
Beata M
BM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium