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. 2006 Apr;116(4):1005-15.
doi: 10.1172/JCI22811.

Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload

Timothy D O'Connell  1 , Philip M Swigart, M C Rodrigo, Shinji Ishizaka, Shuji Joho, Lynne Turnbull, Laurence H Tecott, Anthony J Baker, Elyse Foster, William Grossman, Paul C Simpson
Affiliations

Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload

Timothy D O'Connell et al. J Clin Invest. 2006 Apr.

Abstract

An alpha1-adrenergic receptor (alpha1-AR) antagonist increased heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to alpha1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main alpha1-AR subtypes in the heart, alpha 1A (Adra1a) and alpha 1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and beta-AR stimulation, and beta-ARs were desensitized. Thus, alpha1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that alpha1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of alpha1-antagonists in clinical trials are due to loss of alpha1-signaling in myocytes, emphasizing concern about clinical use of alpha1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.

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Figures

Figure 1
Figure 1. Dilated cardiomyopathy after TAC by echocardiography.
Conscious mice were studied 2 weeks after TAC or sham operation. Ventricular volumes (A and B) were calculated by the cubed method (volume = 1.047 × LV internal dimension3), where LV internal dimension is defined as the distance between the LVFW and the IVS on a 2-dimensionally guided M-mode echocardiogram, and ejection fraction (C) was determined by the formula (end-diastolic volume – end-systolic volume)/end-diastolic volume × 100 (85, 86). Numbers of mice are indicated.
Figure 2
Figure 2. Remodeling in ABKO mice that survived and that died after TAC.
Echocardiography was done on 8 conscious ABKO mice before TAC (day 0) and on days 3 and 7 after TAC. Of the 8 ABKO mice, 4 survived at least 3 weeks, and 4 died between 1 and 3 weeks. Echocardiography results from surviving and dying mice over the first week are shown and were compared by 2-way ANOVA. End-diastolic volume (A), end-systolic volume (B), ejection fraction (C), and pressure gradient (G) changed significantly over time in both groups (*P value given), but heart rate (D), stroke volume (E), and cardiac output (F) did not change. There were no significant differences between the 2 groups on any da
Figure 3
Figure 3. Heart and myocyte size and fibrosis.
Measurements were made 2 weeks after TAC or sham surgery. (A) Left: Heart coronal sections stained with H&E. Magnification, ×25. Right: Heart wet weight/body weight ratio (HW/BW). (B) Left: Ventricular sections stained with FITC-conjugated wheat germ agglutinin and Hoechst 33342. Magnification, ×400. Right: Myocyte cross-sectional area from at least 200 myocytes per heart in randomly selected fields. (C) Left: Ventricular sections stained with fast green and Sirius red for collagen. Magnification, ×400. Right: Interstitial fibrosis as a percentage of total microscopic area from at least 12–14 fields per heart. Numbers of hearts are indicated on the bars.
Figure 4
Figure 4. Fetal gene induction after TAC.
(A) Total RNA extracted from 3 hearts in each group 4 weeks after TAC or sham surgery was used in ribonuclease protection assay for ANF, αMyHC, βMyHC, SERCA, SkAct, and 18S RNAs. (B) PhosphorImager values for the mRNA levels in A, normaliz to 18S.
Figure 5
Figure 5. Apoptosis in heart.
(A) Hearts at 2 weeks after TAC or sham surgery were analyzed by TUNEL staining. TUNEL-positive nuclei in TAC hearts are stained pink (arrows); membranes are green (FITC-conjugated wheat germ agglutinin), and nuclei are blue (Hoechst 33342). Magnification, ×400. (B) TUNEL staining was quantified in 3,000 nuclei from 10 or more randomly selected fields per heart. Numbers of hearts are indicated, and matched areas from the LV, IVS, and RV were sampled in every heart. (C) Phospho-PKCδ was assayed 1 week after TAC or sham surgery by Western blot on extracts from 3 hearts per group. An antibody against total PKCδ gave the same pattern, but background was higher (data not shown). Full-length and cleaved PKCδ are indicated.
Figure 6
Figure 6. Apoptosis in cultured myocytes.
(A) Cultured adult mouse myocytes from WT and ABKO hearts without prior TAC were treated for 2 hours with 200 nM NE or vehicle and visualized by phase-contrast or fluorescence microscopy for annexin V staining, a marker for apoptosis. Magnification, ×100. Note for ABKO myocytes the overall smaller myocyte size by phase contrast and the increased annexin V staining after NE. (B) Annexin V–positive myocytes were quantified as percentage of total myocytes after treatment for 2 hours with 10 μM H2O2, 1 μM ISO, or 200 nM NE. Values are from 2 (H2O2) or 3 (ISO, NE) experiments with myocytes from different hearts.
Figure 7
Figure 7. β-ARs in heart and myocytes.
(A and B) β-AR mRNA and protein levels and cAMP signaling were assayed in ABKO hearts (A) and isolated myocytes (B) without prior TAC, and ratios of mean values are plotted (ABKO/WT). (C and D) Dose-response curves for ISO stimulation of LVSP (C) and LVEDP (D). The ratios of EC50 values are plotted in A. See Results for absolute values.
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