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Ossabaw miniature swine models with mutant vs. non‐mutant AMP kinase alleles for study of electrocardiographic properties during myocardial ischemia
Author(s) -
Chawla Aarti,
Spencer Stephen,
McKenney Mikaela L,
Schultz Kyle A,
Byrd James,
Alloosh Mouhamad,
Mather Kieren,
Sturek Michael
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1135.1
Subject(s) - ampk , mutant , ischemia , medicine , cardiology , protein kinase a , endocrinology , kinase , biology , microbiology and biotechnology , biochemistry , gene
Myocardial ischemia activates AMP kinase (AMPK), which modulates electrophysiology. A spontaneous point mutation from Val199→Ile in the AMPK γ3 subunit of Ossabaw swine impairs AMPK function. We hypothesized that ischemia would elicit greater electrocardiographic ST segment elevation (STE) in AMPK mutant compared to non‐mutant swine. Ischemia induced by balloon occlusion of the circumflex artery was verified by angiography. AMPK mutants showed significant STE within 3 min of ischemia, while non‐mutants showed an STE of ~2mm during 15 min of ischemia. Percent survival to the STE criterion was greater in non‐mutants vs. mutants (p<0.05). Intracoronary infusion of the AMPK activator AICAR (0.5 mM) for 10 min before coronary occlusion reduced profound STE in AMPK mutants, but completely prevented STE in non‐mutants. Percent survival to the STE criterion again was greater in non‐mutants vs. mutants during ischemia. Compound C, an inhibitor of AMPK, trended to decrease time to reach STE criterion compared to AICAR. Metabolic syndrome induced by hypercaloric atherogenic diet was similar in mutants and non‐mutants. Mutants reached the STE criterion in 4 min, but the non‐mutants did not in the 15 min occlusion, thus showing a striking cardiac phenotype. In conclusion, a functional cardiac AMPK and pharmacological AMPK activation decrease ischemia‐induced ST segment elevation. (Support: NIH HL062552)