Adaptation to exercise-induced stress is not dependent on cardiomyocyte α1A-adrenergic receptors

Abstract

The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β 1 -adrenergic receptor subtype. However, the role of the α 1A -adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α 1A -adrenergic receptor knock-down mouse model, challenged mice to four weeks of endurance swim training and assessed cardiac outcomes. With 4-OH tamoxifen treatment, expression of the α 1A -adrenergic receptor was knocked down by 80-89%, without any compensatory changes in the expression of other adrenergic receptors, or changes to baseline cardiac structure and function. Swim training caused eccentric hypertrophy, regardless of genotype, demonstrated by an increase in heart weight/tibia length ratio (30% and 22% in vehicle-and tamoxifen-treated animals, respectively) and an increase in left ventricular end diastolic volume (30% and 24% in vehicle-and tamoxifen-treated animals, respectively) without any change in the wall thickness/chamber radius ratio. Consistent with physiological hypertrophy, there was no increase in fetal gene program (Myh7, Nppa, Nppb or Acta1) expression. In response to exercise-induced volume overload, stroke volume (39% and 30% in vehicleand tamoxifen-treated animals, respectively), cardiac output/tibia length ratio (41% in vehicle-treated animals) and stroke work (61% and 33% in vehicle-and tamoxifen-treated animals, respectively) increased, regardless of genotype. These findings demonstrate that cardiomyocyte α 1A -adrenergic receptors are not necessary for cardiac adaptation to endurance exercise stress and their acute ablation is not deleterious.

Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis

“…Here we have created a cardiomyocyte-specific α1A-AR knockout mouse line to avoid the potentially confounding effects of either supraphysiological protein abundance in the heart or systemic effects from global deletion of a widely expressed receptor. Our cmAKO mice have normal basal cardiac structure and function ( Figure 1 , Table 1 ), similar to both the global α1A-KO mice(19) and to a recently published line with inducible cardiomyocyte-specific α1A-AR deletion(39). Though deletion of cardiomyocyte α1A-ARs does not alter basal phenotype appreciably, it does confer significantly enhanced susceptibility to injury, as evidenced by 50% mortality within 5 days of MI.…”

“…We also cannot exclude the possibility that developmental effects contributed to the exaggerated susceptibility to injury in our cmAKO mice. In this regard, it would be interesting to study the response in a conditional knock down model such as the one created by Graham and colleagues recently (39). A conditional model knockout model would have better fidelity to human -blocker exposure and would allow for explication of the role of 1A-ARs in the more remote post-infarct period.…”

“…The copyright holder for this preprint this version posted August 29, 2022. ; https://doi.org/10.1101/2022.08.29.505687 doi: bioRxiv preprint response in a conditional knock down model such as the one created by Graham and colleagues recently (39). A conditional model knockout model would have better fidelity to human -blocker exposure and would allow for explication of the role of 1A-ARs in the more remote post-infarct period.…”

Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha1-adrenoceptors to early cardiac stress responses

“…In contrast to β 1 -ARs, substantial evidence points to a protective role of at least the α 1A -subtype in cardiac diseases [ 12 , 13 , 78 ]. α 1 -ARs have been described as mediators of physiological hypertrophy [ 51 ], although their involvement remains controversial [ 31 ], and as an essential component of cardiac contractility especially during β 1 -AR desensitization [ 28 , 58 ]. However, α 1 -ARs are G q -protein-coupled receptors and therefore associated with the activation of transcriptional pathways shared by other GPCRs like the angiotensin II type 1 receptor (AT 1 R) and endothelin-1 receptors [ 40 , 69 ].…”

β2-Adrenoceptor Deficiency Results in Increased Calcified Cartilage Thickness and Subchondral Bone Remodeling in Murine Experimental Osteoarthritis

“…However, articular cartilage tissue of Adrb2 -/mice did not show a higher degree of degeneration. One reason for this phenomenon might be the lower expression of a2-AR in the cartilage of Adrb2 -/mice, although most existing studies investigating murine AR knockout models rather described that the deficiency of one AR subtype is not compensated by the up-or downregulation of other AR subtypes (36)(37)(38)(39).…”