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Consequences of Enhanced CGRP Receptor Signaling on Cardiac Function and Mortality Post‐Myocardial Infarction
Author(s) -
Peotta Veronica A,
Weiss Robert M,
Zimmerman Kathy A,
Lu Yongjun,
Russo Andrew F,
Abboud Francois M,
Chapleau Mark W
Publication year - 2010
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.24.1_supplement.1037.4
Subject(s) - medicine , calcitonin gene related peptide , myocardial infarction , ejection fraction , endocrinology , cardiology , cardiac function curve , receptor , heart failure , neuropeptide
Calcitonin gene‐related peptide (CGRP) is a powerful vasodilator released from cardiac sensory nerves post‐myocardial infarction (MI). We have shown that ubiquitous overexpression of the CGRP receptor subunit Receptor Activity‐Modifying Protein 1 (RAMP1) enhances CGRP receptor signaling and attenuates angiotensin‐induced hypertension (J Neurosci 2007, Hypertension 2007) . We hypothesized that transgenic expression of RAMP1 will improve cardiac function and prolong survival post‐MI. RAMP1 mice (n=28) and littermate controls (n=22) underwent left coronary ligation or sham surgery at 12–15 wks of age. Control mice with MI (15–19 wks post‐surg) exhibited left ventricular (LV) dysfunction (echocardiogram), cardiac hypertrophy, decreased wheel‐running activity (revs/hr) and 50% mortality ( Table, *P<.05). RAMP1 mice were not protected post‐MI; LV ejection fraction (LVEF) was reduced, heart weight/body weight (HW/BW, mg/g) was increased, MI size was increased (64±4 vs. 44±3 %), and mortality was increased (67% vs. 50%)(†P<.05 vs. controls). Interestingly, the MI‐induced decrease in wheel‐running was abrogated in RAMP1 mice ( Table).LVEF HW/BW ActivitySham (S) n=10 .76±.03 4.8±0.2 296±79 MI n=7 .49±.06* 6.1±0.3* 127±45* RAMP1‐S n=8 .70±.03 5.8±0.2 245±121 RAMP1‐MI n=6 .27±.03*† 8.3±0.9*† 392±137†We conclude: 1) RAMP1 mice are not protected post‐MI, but instead exhibit marked LV dysfunction and increased mortality; and 2) Despite LV dysfunction, wheel‐running activity is preserved post‐MI in RAMP1 mice. Ubiquitous RAMP1 overexpression may lead to deleterious actions of CGRP that compromise cardiac function. Thus, tissue‐selective targeting of RAMP1 may be critical for therapeutic benefit. (AHA‐0855944G, RR017369 , HL14388, VA)