Spacial and Temporal Patterns of Gene Expression After Cardiac MEK1 Gene Transfer Improve Post-Infarction Remodeling Without Inducing Global Hypertrophy.
Alteration of mitogen activated protein (MAP) kinase signaling in transgenic mice can ameliorate post-myocardial infarction (MI) remodeling. However, pre-existing changes in transgenic hearts and clinically unrealistic transgene expression likely affect the response to injury; it is unknown whether clinically relevant induction of transgene expression in an otherwise normal heart can yield similar benefits. Constitutively active MEK1 (aMEK1) or LacZ adeno-associated virus 9 (AAV9) vectors were injected into the left ventricular (LV) chambers of mice either just before or after coronary ligation. Hearts were evaluated via Western blot, quantitative polymerase chain reaction, histology, and echocardiography. AAV9-mediated aMEK1 delivery altered ERK1/2 expression/activation as in transgenic mice. Transgene expression was not immediately detectable but plateaued at 17 days, and therefore did not likely impact acute ischemia as it would in transgenics. With AAV9-aMEK1 injection just prior to MI, robust expression in the infarct border zone during post-MI remodeling increased border zone wall thickness and reduced infarct size versus controls at 4 weeks, but did not induce global hypertrophy. Significant improvements in local and global LV function were observed, as were trends toward a preservation of LV volume. Delivery after ligation significantly lowered transgene expression in the infarct border zone and did not yield structural or functional benefits. The primary benefits observed in transgenic mice, ameliorated remodeling, and reduced chronic infarct size, were achievable via clinically relevant gene transfer of aMEK1, supporting ongoing translational efforts. Important differences, however, were observed, and consideration must be given to the timing and distribution of transgene delivery and expression. J. Cell. Biochem. 118: 775-784, 2017. © 2016 Wiley Periodicals, Inc.
['Fan|Yanying|Y|', 'Yang|Yi-Lin|YL|', 'Yeh|Che-Chung|CC|', 'Mann|Michael J|MJ|']
D000818:Animals D006332:Cardiomegaly D000229:Dependovirus D020869:Gene Expression Profiling D018014:Gene Transfer Techniques D015316:Genetic Therapy D005822:Genetic Vectors D006801:Humans D048369:MAP Kinase Kinase 1 D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009203:Myocardial Infarction D009206:Myocardium D011994:Recombinant Proteins D020257:Ventricular Remodeling
REMODELING HYPERTROPHY ADENO-ASSOCIATED VIRUS 9 MITOGEN ACTIVATED PROTEIN KINASE MYOCARDIAL INFARCTION