Features Efect of CaMKIIδ Deletion on Sarcomere Structure Tik-Chee (Jenny) Cheng, Sukriti Dewan, Andrew McCulloch, Jef Omens
Jenny Cheng is a senior at Earl Warren College majoring in Bioengineering with a focus in Biotechnology. In Fall 2015, she will be pursuing her PhD in Biomedical Engineering at the University of Wisconsin-Madison, studying cardiovascular pathophysiology for clinical applications.
Heart failure, a progressive cardiomyopathy, a condition with condition that is typically enlarged left ventricles and/or undetected and often dilated ventricular walls that can misdiagnosed, is the leading lead to dysfunction and inadequate cause of deaths around pumping of blood to the rest of the world. The disorder is the body. Calcium/calmodulin- CaMKII isoform (CaMKIIδ) characterized by the inability dependent protein kinase II appear to be protected of the heart to keep up with (CaMKII) is a protein kinase from such dysfunction and the body’s demand for blood that can phosphorylate many hypertrophy. circulation. It is initiated substrates and regulates a wide by structural and functional range of cellular function. Its role Normal myocardial function changes from in calcium signaling is dependent on the structure The disorder is molecular to pathways has been of cardiomyocytes, specifcally systemic levels characterized by implicated in the the basic subunits of muscle that result in the inability of the pathophysiology called sarcomeres. Sarcomeres compensatory cardiac pump to of adverse cardiac contract and generate force physiological keep up with the left ventricular by utilizing the motor changes, body’s demand. remodeling. movements of thin and thick commonly Animal models flaments, specifcally myosin termed cardiac remodeling. At with hypertrophied myocardium heads and actin flaments. frst, this remodeling enables showed increased activity In the intact myocardium, the heart to increase its and expression of CaMKIIδ. sarcomere length change is cardiac output to compensate Genetically altered mice models assumed to be proportional for the change. However, over with a knockout (KO) elimination to muscle cell length changes. time, remodeling results in of the most abundant cardiac This relationship between
11 equilibrium cell length and sarcomere length both CaMKIIδ KO and WT hearts the contracted state. Due to is directly proportional to a to stimulate end-systole. This the varied results of lattice decrease in lattice spacing of process allows visualization spacing, further research, such the myosin-actin flaments as of how CaMKIIδ afects heart as a more direct approach for the heart cells, along with the contraction. Image analysis measuring sarcomere length sarcomeres, are stretched. By indicates that sarcomere length and lattice spacing, is needed measuring sarcomere length and and myosin-myosin flament to understand how loss of lattice spacing in cardiomyocyte- spacing from TEM were greater CaMKIIδ afects the structure specifc CaMKIIδ KO mice and in the CaMKIIδ KO versus WT and function of the heart. Such wild type (WT) mice (control hearts fxed in the relaxed state. studies will allow for a better group), it is then possible to This fnding indicates that the understanding of how CaMKII determine how CaMKIIδ KO contracture solution stimulates can be regulated for prevention cells change in length and how contraction at the molecular or treatment of cardiac physiological forces develop. level, which is the desired efect. hypertrophy and ultimately, Lattice spacing of the myosin- heart failure. To measure sarcomere length actin flaments in CaMKIIδ KO and lattice spacing, transmission and WT hearts varied between electron microscopy (TEM) was the relaxed and contracted states. used to image the sarcomeres Lattice spacing was greater and myosin-actin flaments of in the CaMKIIδ KO versus the heart. A contracture solution WT heart fxed in the relaxed containing barium chloride and state and smaller in CaMKIIδ adenosine was used to perfuse KO versus WT hearts fxed in
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Volume 1/ Spring 2015 12