Scientists from the Baylor College of Medicine and the Tx Heart Institute studying pathways underlying heart cell features say they have discovered a previously unknown connection among processes that keep the heart from repairing itself. This particular finding (“Dystrophin glycoprotein complex sequesters Yap to prevent cardiomyocyte proliferation”), published in Character , may lead to new approaches that will promote heart cellular renewal in the future.
“We are investigating problem of why the heart muscle doesn’t renew, ” states senior author James Martin, M. D., Ph. G., professor and Vivian L. Smith Chair in Regenerative Medicine at Baylor College of Medicine. “In this particular study, we focused on two pathways of cardiomyocytes or even heart cells; the Hippo pathway, which is involved in ending renewal of adult cardiomyocytes, and the dystrophin glycoprotein complicated (DGC) pathway, essential for cardiomyocyte normal functions.
“We are also interested in studying mutations in DGC parts because patients with these mutations have a muscle wasting illness called muscular dystrophy. ”
Previous function suggested that components of the DGC pathway may in some way interact with members of the Hippo pathway. In this study, Doctor Martin and colleagues studied the consequences of this interaction within animal models. The investigators genetically engineered mice in order to lack genes involved in one or both pathways, and then driven the ability of the heart to repair an injury. These studies demonstrated for the first time that dystroglycan 1, a component of the DGC path, directly binds to Yap, a part of the Hippo path, and that this interaction inhibited cardiomyocyte proliferation.
“We found that the DGC component dystroglycan one (DAG1) directly binds to Hippo pathway effector Yap to inhibit [cardiomyocyte] proliferation. The Yap-DAG1 interaction was enhanced by Hippo-induced Yap phosphorylation, exposing a connection between Hippo pathway function and the DGC, inch write the researchers. “After injury, Hippo-deficient postnatal minds maintained organ size control by repairing the problem with correct dimensions, whereas postnatal hearts doubly lacking for Hippo and the DGC showed CM overproliferation in the injury site. In mature Mdx mouse hearts— a model of DMD— Hippo deficiency secured against overload-induced heart failure. ”
“The discovery that the Hippo and the DGC pathways connect within the cardiomyocyte and that together they act as ‘brakes’ or end signals to cell proliferation opens the possibility that by disrupting this interaction one day it might be possible to help adult cardiomyocytes proliferate and heal injuries caused by a heart attack, for example , inch notes Dr . Martin, who adds that another extensive application of this discovery could be to improve cardiac function within children with muscular dystrophy.
“Patients along with muscular dystrophy can have severe reduction in cardiac function, inch according to Dr . Martin. “Our findings may help to design medications to slow down cardiac decline in muscular dystrophy simply by stimulating cardiomyocyte proliferation. In order to do that, we need more study to understand cardiomyocyte growth control pathways in greater fine detail. ”