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Cardiac response to adrenergic stress differs by sex and across the lifespan.

ABSTRACT: The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact adrenergic-mediated cardiac function remain poorly described. In the current investigation, we compared the cardiac response to adrenergic stress to gain mechanistic understanding of how the response to an adrenergic challenge differs by sex and age. Juvenile (4 weeks), adult (4-6 months), and aged (18-20 months) male and female mice were treated with the β-agonist isoproterenol (ISO) for 1 week. ISO-induced morphometric changes were age- and sex-dependent as juvenile and adult mice of both sexes had higher left ventricle weights while aged mice did not increase cardiac mass. Adults increased myocyte cell size and deposited fibrotic matrix in response to ISO, while juvenile and aged animals did not show evidence of hypertrophy or fibrosis. Juvenile females and adults underwent expected changes in systolic function with higher heart rate, ejection fraction, and fractional shortening. However, cardiac function in aged animals was not altered in response to ISO. Transcriptomic analysis identified significant differences in gene expression by age and sex, with few overlapping genes and pathways between groups. Fibrotic and adrenergic signaling pathways were upregulated in adult hearts. Juvenile hearts upregulated genes in the adrenergic pathway with few changes in fibrosis, while aged mice robustly upregulated fibrotic gene expression without changes in adrenergic genes. We suggest that the response to adrenergic stress significantly differs across the lifespan and by sex. Mechanistic definition of these age-related pathways by sex is critical for future research aimed at treating age-related cardiac adrenergic desensitization.

SUBMITTER: Yusifov A

PROVIDER: S-EPMC8492879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case-control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.

Project description:AimsTo determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.Methods and resultsReplacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca(2+)]i, and sarcoplasmic reticulum (SR) Ca(2+) content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and the Na(+)/Ca(2+) exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.ConclusionIn young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.

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Cardiac response to adrenergic stress differs by sex and across the lifespan.

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