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Cell therapy rescues aging-induced beta-1 adrenergic receptor and GRK2 dysfunction in the coronary microcirculation

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Abstract

Our past study showed that coronary arterioles isolated from adipose-derived stromal vascular fraction (SVF)–treated rats showed amelioration of the age-related decrease in vasodilation to beta-adrenergic receptor (β-AR) agonist and improved β-AR-dependent coronary flow and microvascular function in a model of advanced age. We hypothesized that intravenously (i.v.) injected SVF improves coronary microvascular function in aged rats by re-establishing the equilibrium of the negative regulators of the internal adrenergic signaling cascade, G-protein receptor kinase 2 (GRK2) and G-alpha inhibitory (Gαi) proteins, back to youthful levels. Female Fischer-344 rats aged young (3 months, n = 24), old (24 months, n = 26), and old animals that received 1 × 107 green fluorescent protein (GFP+) SVF cells (O + SVF, n = 11) 4 weeks prior to sacrifice were utilized. Overnight urine was collected prior to sacrifice for catecholamine measurements. Cardiac samples were used for western blotting while coronary arterioles were isolated for pressure myography studies, immunofluorescence staining, and RNA sequencing. Coronary microvascular levels of the β1 adrenergic receptor are decreased with advancing age, but this decreased expression was rescued by SVF treatment. Aging led to a decrease in phosphorylated GRK2 in cardiomyocytes vs. young control with restoration of phosphorylation status by SVF. In vessels, there was no change in genetic transcription (RNAseq) or protein expression (immunofluorescence); however, inhibition of GRK2 (paroxetine) led to improved vasodilation to norepinephrine in the old control (OC) and O + SVF, indicating greater GRK2 functional inhibition of β1-AR in aging. SVF works to improve adrenergic-mediated vasodilation by restoring the β1-AR population and mitigating signal cascade inhibitors to improve vasodilation.

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Abbreviations

BF:

blood flow

HF:

heart failure

β-AR:

beta-adrenergic receptor

α-AR:

alpha-adrenergic receptor

AC:

adenylyl cyclase

Gαi:

alpha subunit of inhibitory G-protein

Gs:

stimulatory G-protein

GRK:

G-protein receptor kinase

i.v.:

intravenous

SVF:

adipose-derived stromal vascular fractions

CFR:

coronary flow reserve

YC:

young control

OC:

old control

GFP+:

transgenic green fluorescent protein positive

O + SVF:

old treated with adipose-derived stromal vascular fractions

LAD:

left anterior descending coronary artery

PSS:

physiological salt solution

NE:

norepinephrine

Parox:

paroxetine HCl

NaF:

sodium fluoride

CPG:

CPG20712A

Dob:

dobutamine

ICI:

ICI118551

SNP:

sodium nitroprusside

RT:

room temperature

ROI:

region of interest

LV:

left ventricular

BW:

body weight (grams)

Epi:

epinephrine

5HT:

serotonin

DA:

dopamine

5-HIAA:

metabolite of serotonin

Dmax:

maximum diameter (μm)

P-GRK2:

phosphorylated G-protein receptor kinase 2

Gnαo1:

G-protein subunit alpha-o1

Gnαi2:

G-protein subunit alpha-i2

Sgsm2:

small G-protein signaling modulator-2

AC6:

adenylyl cyclase isoform 6

CVD:

cardiovascular disease

CMD:

coronary microvascular disease

MI:

myocardial ischemia

MSC:

mesenchymal stem cell

NO:

nitric oxide

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Acknowledgements

The authors wish to thank the University of Missouri Rat Resource & Research Center (P40OD011062) for the initial GFP+ Fischer-344 breeding pairs, the University of Louisville Bioanalytical Core for urine catecholamine level testing, the University of Louisville Genomics Core for the RNA sequencing, and the University of Louisville Bioinformatics core for the library analysis. The authors also wish to thank Drs. Nolan Boyd and Natia Kelm for their technical expertise and Ms. Michaela Dukes for technical support in western blotting, and Ms. Virginia Steilberg for technical support with isolated coronary arteriole experiments.

Funding

This research was funded by the National Institutes of Health (R01 AG053585), Department of Defense (W81XWH-19-RTRP-IDA and W81XWH-13-2-0057), and the Gheen’s Foundation.

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Authors and Affiliations

  1. Cardiovascular Innovation Institute, University of Louisville, 302 E Muhammad Ali Blvd, Louisville, KY, 40202, USA

    Gabrielle Rowe, Evan Tracy, Jason E. Beare & Amanda J. LeBlanc

  2. Department of Physiology, University of Louisville, Louisville, KY, 40292, USA

    Gabrielle Rowe, Evan Tracy & Amanda J. LeBlanc

  3. Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40292, USA

    Jason E. Beare

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  1. Gabrielle Rowe
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Correspondence to Amanda J. LeBlanc.

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The authors have no conflicts of interest to declare. All animal surgeries were performed in accordance with protocols approved by the University of Louisville Institutional Animal Care and Use Committee (IACUC-approved protocol #19635) and the NIH Guide for the Care and Use of Laboratory Animals.

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Supplementary Information

Supplemental Fig. 1

Contribution of the β-2 Adrenergic Receptor to Adrenergic-Dependent Vasodilation. Using pressure myography, isolated coronary microvessels from YC, OC, and O+SVF animals were subjected to β-AR agonism with NE with and without the β2-AR inhibitor ICI118551 (a-c) or dobutamine with and without the β2-AR inhibitor ICI118551 (d-f). Data are presented as means±SEM. Significance defined by paired pre- to post-inhibition for analysis using Two-Way Repeated Measures ANOVA with Bonferroni post hoc testing. p≤.05 when pre- vs. post-inhibition (*). (PNG 134 kb)

High Resolution (TIF 36938 kb)

Supplemental Fig. 2

Contribution of the β-3 Adrenergic Receptor and cAMP to Adrenergic-Dependent Vasodilation. BRL-37344, a β3-AR agonist (a), and 8-Bromo-cAMP, a cAMP donor (b), were added in a dose-dependent manor to isolated coronary microvessels from YC, OC, and O+SVF animals via pressure myography. Data presented as means±SEM. Significance determined as p<.05 when vs. YC (*) and vs. OC (#) utilizing Two-Way Repeated Measures ANOVA with Bonferroni post hoc analysis. (PNG 110 kb)

High Resolution (TIF 36937 kb)

Supplemental Table 1

RNA transcripts. List of RNA transcripts and expression of differentially expressed genes in isolated coronary microvessels from YC, OC, and O+SVF samples. Significance defined as cuffdiff and DESeq2 for cutoff p<.05. (DOCX 2343 kb)

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Rowe, G., Tracy, E., Beare, J.E. et al. Cell therapy rescues aging-induced beta-1 adrenergic receptor and GRK2 dysfunction in the coronary microcirculation. GeroScience 44, 329–348 (2022). https://doi.org/10.1007/s11357-021-00455-6

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