ORIGINAL ARTICLE
PPARa Stimulation Modulates Myocardial
Ischemia-induced Activation of Renin–Angiotensin System
Luz Ibarra-Lara, PhD,*† María Sánchez-Aguilar, MSc,* Enrique Hong, MD, PhD,†
Leonardo del Valle-Mondragón, BS,* Elizabeth Soria-Castro, MSc,‡ Francisca Pérez-Severiano, PhD,§
Juan Carlos Torres-Narváez, MSc,* Margarita Ramírez-Ortega, PhD,*
Gustavo S. Pastelín-Hernández, MD,* Luz G. Cervantes-Pérez, PhD,* and Alicia Sánchez-Mendoza, PhD*
Abstract: We have recently demonstrated that peroxisome
proliferator–activated receptor alpha (PPARa) stimulation lowers the
production of angiotensin II while increasing the production of Ang-
(1–7), both in cardiac and plasmatic level. This stimulation improves
nitric oxide bioavailability, preserving cardiac histologic features and
functioning. Based on these results, we decided to study the effect of
PPARa stimulation on renin–angiotensin system components of ische-
mic myocardium. Male Wistar rats (weighing 300–350 g) were as-
signed to the following groups: (1) sham, (2) myocardial ischemia
vehicle–treated (MI-V), and (3) myocardial ischemia clofibrate–treated.
Expression of the angiotensin-converting enzyme increased during
ischemia, whereas clofibrate-treated group remained comparable to
control. Activation of the PPARa receptor stimulated the expression
of angiotensin-converting enzyme-2; while the activity of this enzyme
was increased in MI-V, clofibrate inhibited any change. The concen-
tration of bradykinin and phospho-Akt
SER473
in homogenate increased
in the animals treated with the drug. Mas receptor expression increased
in MI-V rats. In conclusion, stimulation of PPARa by clofibrate pre-
vents an increase in the activity of renin–angiotensin system and pro-
motes the production of vasodilator substances.
Key Words: PPARa, ACE, ACE-2, bradykinin, Akt
(J Cardiovasc Pharmacol Ô 2015;65:430–437)
INTRODUCTION
The renin–angiotensin system (RAS) is a highly impor-
tant regulator of cardiovascular performance. The majority of
physiological effects of RAS are mediated by angiotensin II
(AngII) through AngII type 1 (AT
1
) and AngII type 2 (AT
2
)
receptors.
1
The AT
1
receptor is involved in the classical ac-
tions of AngII: vasoconstriction, inflammation, cell growth,
apoptosis, fibrogenesis, increased sympathetic activity, and
increased rate and force of contraction of the heart. The
AT
2
receptor counteracts AT
1
receptor actions and mediates
the activation of kinin/nitric oxide (NO)/cyclic guanosine
monophosphate system in the rat heart.
2
At systemic level, AngII production is initiated by the
action of renal renin over angiotensin, produced by the liver,
rendering angiotensin I (AngI). This latter peptide may be
metabolized by angiotensin-converting enzyme (ACE) to
synthesize the vasoactive peptide, AngII. It is noteworthy
that AngI may be a substrate of other enzymes, the neutral
endopeptidase and prolyl endopeptidase, giving rise to
angiotensin-(1–7) [Ang-(1–7)]. However, AngII may also
be transformed into Ang-(1–7) by the action of ACE-2.
3
Recently, we demonstrated
4
that animals subjected to
2 hours of myocardial ischemia (MI) increased the production
of plasmatic and tissue AngII, as well as the expression of
AT
1
receptor, leading to structural and hemodynamic
changes. However, recent research indicates that the pressor
and proliferative actions of AngII may be counteracted by the
action of Ang-(1–7) and bradykinin (BK), mainly through the
action of NO.
3
BK may potentiate the activity of Ang-(1–7)
leading to several actions. These include Ang-(1–7)-induced
ACE inhibition
5
and also potentiating the vasodilator effects
of BK. This was demonstrated by Almeida et al on injecting
a bolus of BK into isolated perfused rat hearts or into isolated
canine coronary arteries. They found that the effect of BK
was potentiated by Ang-(1–7),
6
and Ang-(1–7)-induced relax-
ation was attenuated by N
G
-nitro-L arginine, a NO synthase
inhibitor, and by the specific kinin B
2
receptor blocker HOE
140.
7
According to Loot et al,
8
chronic infusion of Ang-(1–7)
improved endothelial aortic function and coronary perfusion
and preserved cardiac function in an experimental rat model
of heart failure induced by ligation of the left coronary artery.
Ang-(1–7) also exerts a cardioprotective role. The
reported target molecules for Ang-(1–7) actions are the G-
protein–coupled Mas and AT
2
receptors.
9
This is supported
by the fact that many cardiovascular effects of Ang-(1–7) are
blocked by A-779, a selective Mas receptor antagonist.
6
Also
supporting the role of Ang-(1–7) as cardioprotector, the ex
Received for publication April 2, 2014; accepted October 28, 2014.
From the *Department of Pharmacology, National Institute of Cardiology
“Ignacio Chávez,” Mexico City, Mexico; †Department of Neuropharma-
cology and Experimental Therapeutics, Research and Advanced Studies
Center of the National Polytechnic Institute (CINVESTAV-IPN), Mexico
City, Mexico; ‡Department of Pathology, National Institute of Cardiology
“Ignacio Chávez” Mexico City, Mexico; and §Department of Neurochem-
istry, National Institute of Neurology and Neurosurgery “Manuel Velasco
Suárez,” Mexico City, Mexico.
The authors report no conflicts of interest.
Reprints: Alicia Sánchez-Mendoza, PhD, Department of Pharmacology, In-
stituto Nacional de Cardiología “Ignacio Chávez,” Juan Badiano No. 1,
Col. Sección XVI, Tlalpan, 14080 México, D.F., México (e-mail:
masanchez@gmail.com).
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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