title: Maintaining serum response factor activity in the older heart equal to that of the young adult is associated with better cardiac response to isoproterenol stress.
abstract: To understand the effect of transcription regulation in modulating cardiac aging, we sought to study the role of serum response factor (SRF), a key transcription factor in the heart that is normally increased with senescence and also in congestive heart failure. A Tet-Off gene expression system was used for cardiac-specific over-expression of a mutant SRF protein. In these binary transgenic mice, there is no age-related increase in SRF protein expression; in fact, there appeared to be a mild reduction of SRF protein (Mild-R SRF Tg). The older, middle-aged (15 mo) Mild-R SRF Tg mice appeared healthier and were better able to maintain their left ventricular systolic pressure (LVSP) in response to moderate â-adrenergic stimulation compared with age-matched Non-Tg mice, which demonstrated a negative ionotropic response. The Mild-R SRF Tg hearts had lower mRNA expression of BNP (p < 0.05), and the sodium calcium exchanger (p < 0.05), compared to Non-Tg. Mild-R SRF Tg had higher mRNA levels of SERCA2 (p < 0.05) and ryanodine receptor 2 (p < 0.05) compared to Non-Tg hearts. These findings suggest that preventing the age-associated increase in SRF is associated with better preserved intracellular calcium handling and functional response to stress; it might be advantageous for the older adult heart. This mouse model could be helpful in elucidating the molecular mechanisms underlying certain age-related changes in cardiac reserve capacity and response to stress.
authors.affiliation: CAVHS, Little Rock, AR, USA.
authors.forename: Gohar
authors.initials: G
authors.lastname: Azhar
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Sophie
authors.initials: S
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhong
authors.forename: Charles M
authors.initials: CM
authors.lastname: Quick
authors.forename: Jeanne Y
authors.initials: JY
authors.lastname: Wei
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000032:analysis / Q000096:biosynthesis*; D017725:Ventricular Pressure / Q000187:drug effects*
chemical_list: D026362:Serum Response Factor; D007545:Isoproterenol