Abstract
The regulatory function of alpha(1B)-adrenoceptors in mammalian heart homeostasis is controversial. The objective of the present study was to characterize the expression/activity of key proteins implicated in cardiac calcium handling (Na(+)/K(+)-ATPase and Ca(2+)-ATPases) and growth (ERK1/2, JNK1/2 and p38) in mice with cardiac-selective overexpression of constitutively active mutant alpha1B-adrenoceptor (CAMalpha(1B)-AR), which present a mild cardiac hypertrophy phenotype. Immunoblot assays showed that myocardial plasma membrane Ca(2+)-ATPase (PMCA) expression was increased by 30% in CAMalpha(1B)-AR mice (N = 6, P < 0.05), although there was no change in sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2) expression. Moreover, total Ca(2+)-ATPase activity was not modified, but a significant increase in the activity of the thapsigargin-resistant (PMCA) to thapsigargin-sensitive (SERCA) ratio was detected. Neither Na(+)/K(+)-ATPase activity nor the expression of alpha(1) and alpha(2) subunit isoforms was changed in CAMalpha(1B)-AR mouse hearts. Moreover, immunoblot assays did not provide evidence for an enhanced activation of the three mitogen-activated protein kinases studied in this stage of hypertrophy. Therefore, these findings indicate that chronic cardiac alpha(1B)-AR activation in vivo led to mild hypertrophy devoid of significant signs of adaptive modifications concerning primary intracellular calcium control and growth-related proteins, suggesting a minor pathophysiological role of this adrenergic receptor in mouse heart at this stage of development.
Highlights
In mammalian heart, adrenoceptors (AR) mediate myocyte contraction and growth induced by the sympathetic nervous system
Animal model CAMα1B-AR transgenic male adult mice (10 to 12 weeks old; Jackson Laboratory, USA) were maintained and used [7]. They harbored a genetic profile in which the mutant α1B gene was incorporated by non-homologous insertion through the α-myosin heavy chain (α-MHC) promoter coupled to the coding sequence of CAMα1B-AR
An equivalent expression pattern was found for both total and phosphorylated forms of ERK1/2 (WT = 100 ± 11 and CAMα1B-AR = 91 ± 11%, N = 6), JNK1/2 (WT = 100 ± 13 and CAMα1B-AR = 88 ± 9%, N = 6) and p38 (WT = 100 ± 10 and CAMα1B-AR = 106 ± 6%, N = 6; Figure 1). Due to their lower density in mammalian hearts compared to the β-AR and the lack of drugs with suitable selectivity, the role of α1-AR subtypes in cardiac function is still poorly understood
Summary
Adrenoceptors (AR) mediate myocyte contraction and growth induced by the sympathetic nervous system. The β1-AR is the most abundant cardiac AR subtype and its functional importance has been extensively studied [1]. Other AR subtypes are present in the heart and their relevance to pathophysiological conditions has been studied in recent years [2,3]. In vivo unbiased myocardial responses are impossible to evaluate conclusively because of the vasoactive effect of α1-AR agonists. The restricted number of appropriate subtype-selective ligands, especially for α1B-AR [1,2], makes the elucidation of specific effects of different α1-AR challenging. In order to overcome these drawbacks, transgenic mouse models overexpressing distinct myocardial-targeted
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