The Primary Benefits of Angiotensin-Converting Enzyme Inhibition on Cardiac Remodeling Occur During Sleep Time in Murine Pressure Overload Hypertrophy
Open accessAbstract
Objectives Our objective was to test the hypothesis that there is a significant diurnal variation for the therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors on pressure-overload cardiovascular hypertrophy.Background Physiological and molecular processes exhibit diurnal rhythms that may affect efficacy of disease treatment (chronotherapy). Evidence suggests that the heart primarily remodels during sleep. Although a growing body of clinical and epidemiological evidence suggests that the timing of therapy, such as ACE inhibition, alters diurnal blood pressure patterns in patients with hypertension, the benefits of chronotherapy on myocardial and vascular remodeling have not been studied.Methods We examined the effects of the short-acting ACE inhibitor, captopril, on the structure and function of cardiovascular tissue subjected to pressure overload by transverse aortic constriction (TAC) in mice. Captopril (15 mg/kg intraperitoneally) or placebo was administered at either murine sleep time or wake time for 8 weeks starting 1 week after surgery.Results TAC mice given captopril at sleep time had improved cardiac function and significantly decreased heart: body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen versus TAC mice given captopril or placebo during wake time. Captopril induced similar drops in blood pressure at sleep or wake time, suggesting that time-of-day differences were not attributable to blood pressure changes. These beneficial effects of captopril were correlated with diurnal changes in ACE mRNA expression in the heart.Conclusions The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo. These studies support the hypothesis that the heart (and vessels) remodel during sleep time and also illustrate the importance of diurnal timing for some cardiovascular therapies.
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Another study of the ACE inhibitor captopril showed that it reduced blood pressure in mice at all times of day, but improved cardiac function only when administered at sleep time, potentially owing to captopril administration being in phase with increased ACE in the heart, and a consequent time-gated cardiac remodeling.
“Another study of the ACE inhibitor captopril showed that it reduced BP in mice at all times of day, but improved cardiac function only when administered at sleep time, potentially owing to captopril administration being in phase with increased ACE in the heart, and a consequent time-gated cardiac remodeling (179).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [179]
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- Authors
- Martino, T. A., Tata, N., Simpson, J. A., Vanderlaan, R., Dawood, F., Kabir, M. G., Khaper, N., Cifelli, C., Podobed, P., Liu, P. P., Husain, M., Heximer, S., Backx, P. H., & Sole, M. J.
- Affiliations
- University of Guelph (CA)
- University of Toronto (CA)
- Lakehead University (CA)
- Corresponding author
- Sole, Michael J.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 57
- Issue
- 20
- Pages
- 2020-2028
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2141851544
- Cited by
- 94
- References
- 30
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 1 · 2022: 8 · 2021: 10 · 2020: 12 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 7 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Ontario (485506, T4479)
- A. Ephriam and Shirley Diamond Cardiomyopathy Fund
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- ACE inhibitors, captopril, cardiac remodeling, pressure overload, transverse aortic constriction, sleep, chronotherapy, diurnal variation, diurnal cycle, cardiac hypertrophy, perivascular collagen, ACE mRNA expression
- MeSH terms
- Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Pressure, Hypertension, Male, Mice, Inbred C57BL, Sleep, Hypertrophy, Left Ventricular, Ventricular Remodeling, Mice, Drug Chronotherapy
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