Angiotensin-Converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats

Toblli, J

doi:10.1016/j.amjhyper.2003.10.006

Cited by 71Renin-Angiotensin System StudiesAngiogenesis and VEGF in CancerNitric Oxide and Endothelin Effects

Angiotensin-Converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats

Toblli, J·2004·American Journal of Hypertension

DOI 10.1016/j.amjhyper.2003.10.006

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Abstract

BACKGROUND: Obesity, hypertension, and non-insulin-dependent diabetes mellitus (NIDDM) are associated with microvascular rarefaction in the myocardium and this contributes to increase cardiovascular morbidity and mortality. At present, controversial data exist in medical literature regarding the specific role of angiotensin-converting enzyme (ACE) inhibitors concerning angiogenesis in different tissues. The present study was designed to determine the possible beneficial effects of an ACE inhibitor perindopril on myocardial angiogenesis in an animal model of obesity, hypertension, and NIDDM, such as the obese Zucker rat (OZR) and control lean Zucker rats (LZR). METHODS AND RESULTS: Ten-week-old male OZR (fa/fa) and LZR (Fa/fa) were used in this study: OZR group (G1, n = 10), OZR with perindopril group (G2, n = 10); LZR group (G3, n = 10). For 6 months, G2 received a daily dose of 3 mg/kg of perindopril, by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. After 6 months of treatment, all rats were killed, hearts were harvested for pathology studies, including immunohistochemistry, using monoclonal antibodies against rat endothelial cell (RECA-1) and endothelial nitric oxide synthase. At the end of the study, OZR treated with perindopril presented: 1) lower blood pressure (BP) (127 +/- 3.2 v 152.4 +/- 3 mm Hg, P <.01) and 2) lower heart weight/100 g body weight (0.22 +/- 0.02 v 0.36 +/- 0.04 g, P <.01) than OZR untreated. Moreover, OZR that received perindopril showed higher: 1) myocyte density (2044 +/- 67 v 847 +/- 91 myocytes/mm(2), P <.01) and 2) capillary density (1348 +/- 118 v 436 +/- 78 capillaries/mm(2), P <.01); higher amount of: 1) vascular endothelial growth factor (VEGF) in the myocardium (P <.01) and higher percentage of capillaries with positive immunostaining for eNOS (P <.01), compared with untreated OZR. There was a correlation between both the amount of VEGF in myocardium and the number of capillaries (r = 0.88; P <.01) and VEGF and eNOS expression in myocardial capillaries (r = 0.93; P <.01) in OZR treated with perindopril. Finally, OZR that received P showed an improvement in insulin/glucose ratio (P <.01) when compared with untreated OZR. CONCLUSIONS: These results suggest that ACE inhibition by perindopril improves myocardial angiogenesis in this animal model of human metabolic syndrome. The pathway that involves bradykinin, eNOS, and VEGF could be involved in this effect; however, because no additional antihypertensive treatment group was included in our study, the BP-lowering effect cannot be excluded.

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Impaired angiogenic signaling was confirmed in hearts of Zucker rats and in muscle-restricted insulin receptor KO mice lacking myocardial insulin receptor expression.
“Impaired angiogenic signaling was also independently confirmed in the hearts of Zucker rats and in muscle-restricted insulin receptor KO mice that also lack insulin receptor expression in the myocardium (133, 349).”
From Cardiac remodeling in obesity (2008) · cites this paper as [349]

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Takeshita S, Tomiyama H, Yokoyama N, Kawamura Y, Furukawa T, Ishigai Y, Shibano T, Isshiki T, Sato T: Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats. Cardiovasc Res 2001;52: 314 -320.

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Perindopril improves angiogenesis in myocardium of obese zucker rats
Toblli, J. E. (2003) · American Journal of Hypertension · doi:10.1016/s0895-7061(03)00707-6
Self-citation
Do angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers decrease the risk of hospitalization secondary to community-acquired pneumonia? A nested case-control study. Pharmacotherapy
Toblli, J. E., Cao, G., DeRosa, G., Gennaro, F. D., & Forcada, P. (2016)
Self-citation
Angiotensin-Converting Enzyme Inhibition Promotes Coronary Angiogenesis in the Failing Heart of Dahl Salt-Sensitive Hypertensive Rats
Yazawa, H., Miyachi, M., Furukawa, M., Takahashi, K., Takatsu, M., Tsuboi, K., Ohtake, M., Murase, T., Hattori, T., Kato, Y., et al. (2011) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2011.09.002 · Cited by 38 · see citing works
Angiotensin‐Converting Enzyme Inhibition Reduces Lipid Deposits in Myocardium and Improves Left Ventricular Function of Obese Zucker Rats
Toblli, J. E., Cao, G., Rivas, C., DeRosa, G., & Domecq, P. (2006) · Obesity · doi:10.1038/oby.2006.183 · Cited by 12 · see citing works
Self-citation
Reduced cardiac expression of plasminogen activator inhibitor 1 and transforming growth factor β<sub>1</sub> in obese Zucker rats by perindopril
Toblli, J. E., Cao, G., DeRosa, G., & Forcada, P. (2005) · Heart · doi:10.1136/hrt.2003.022707 · Cited by 47 · see citing works
Self-citation

Authors: Toblli, J.
Affiliations: Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
Corresponding author: Toblli, J
ORCID: Toblli, J
Venue: American Journal of Hypertension
Publisher: Oxford University Press (OUP)
Published: 2004-02
Volume: 17
Issue: 2
Pages: 172-180
ISSN: 0895-7061 (ISSN-L)
DOI: 10.1016/j.amjhyper.2003.10.006
OpenAlex: W2035835505
Cited by: 71
References: 55
Citations by year: 2024: 3 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 2 · 2013: 2 · 2012: 4
FWCI: 3.26
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Hypertension (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords: angiotensin-converting enzyme inhibition, perindopril, myocardial angiogenesis, obesity, Zucker rats, hypertension, type 2 diabetes, microvascular rarefaction, endothelial nitric oxide synthase, vascular endothelial growth factor, capillary density, myocardial fibrosis, endothelial cells, blood pressure, heart weight, myocardial infarction, myocardial ischemia
MeSH terms: Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Glucose, Blood Pressure, Coronary Circulation, Disease Models, Animal, Immunohistochemistry, Male, Myocardium, Neovascularization, Pathologic, Obesity, Organ Size, Rats, Zucker, Microvascular Angina, Perindopril, Rats

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Angiotensin-Converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats

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