Heart Views. 2014 Jul-Sep; 15(3): 7476.

doi: 10.4103/1995-705X.144792
PMCID: PMC4268614
Cardioprotective Effects of Ghrelin in Heart
Failure: From Gut to Heart
Mahalaqua Nazli Khatib, Padam Simkhada,1 and Dilip Gode2
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Abstract
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Chronic heart failure (CHF) is a major cause of morbidity and
mortality. Cardioprotective effects of ghrelin, especially in its
acylated form have been demonstrated in heart failure (HF)
models and exploratory human clinical studies. Hence, it has
been proposed for the treatment of HF. However, the underlying
mechanism of its protective effects against HF remains unclear.
Future researches are needed to evaluate the efficacy of Ghrelin
as a new biomarker and prognostic tool and for exploring its
therapeutic potential in patients suffering from CHF.
Keywords: Cardioprotective effects, ghrelin, gut
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INTRODUCTION
Chronic heart failure (CHF) is a major cause of morbidity and
mortality. Apart from the many causes of CHF, a slow reduction
in the number of cardiomyocytes is one of the most important
causative factors.[1] Therefore, inhibiting cardiomyocyte
apoptosis may have implications for the treatment of heart
failure (HF).
Ghrelin
Ghrelin, a gut-derived 28-amino acid peptide hormone was first
identified in 1999 by Kojima as an endogenous ligand for the
GH secretagogue receptor (GHS-R), an endogenous stimulator
of GH and is now implicated in a number of physiological
processes. Cardioprotective effects of ghrelin, especially in its
acylated form have been demonstrated on HF models and
exploratory human clinical studies. Hence, it has been proposed
for the treatment of HF. However, the underlying mechanism of
its protective effects against HF remains unclear.
Cardiovascular Effects of Ghrelin
Clinical studies have reported that ghrelin confers a variety of
potentially beneficial cardiovascular effects, which includes
reduction of mean arterial blood pressure, increase in
myocardial contractility, protection of endothelial cells, and
improvement of energy metabolism of myocardial cells.[2,3]
Exogenous administration of ghrelin also results in
improvement in coronary flow, heart rate, dilatation of
peripheral blood vessels, constriction of coronary arteries, and
improvement in ventricular and endothelial function. Clinical
studies have reported that exogenous administration of ghrelin
decreases muscle wasting, improves exercise capacity, inhibits
cardiomyocyte apoptosis, inhibits sympathetic nerve activity,
and protects from HF induced by myocardial infarction.[4,5,6]
Importantly, administration of ghrelin has been demonstrated to
improve the cardiac function and prognosis in patients suffering
from end-stage CHF.[7] In vitro, ghrelin decreases inotropism
and lusitropism. Ghrelin reverses cardiac cachexia by promoting
a positive energy balance and also by enhancing direct
cardioprotective effects of ghrelin.[8] These cardioprotective
effects are independent of growth hormone release and likely
involve binding to cardiovascular receptors.[9]
There is a widespread distribution of ghrelin and its receptors
(GHSR 1a) in the cardiovascular tissues, which provides a
definitive evidence of its cardiac actions. The protective effects
of ghrelin on heart are mediated through direct effects on the
heart and blood vessel and through its growth-hormone-
releasing effect. In normal individuals, acute increases in ghrelin
do not alter cardiac metabolism, whereas in patients with HF,
they enhance oxidation of free fatty acids and reduce the
oxidation of glucose, thus partly correcting its metabolic
alterations. This interesting mechanism of action of ghrelin may
contribute to the cardioprotective effects of ghrelin in HF.[10]
Ghrelin mediates cardioprotective effects by modulating cardiac
autonomic nervous activity. However; the precise mechanisms
by which ghrelin regulates sympathetic activity are still unclear
and needs further investigation. Peripheral ghrelin may act on
GHSR 1a at the cardiac vagal nerve ending, which goes to the
nucleus of tractus solitarius (NTS) and inhibit the renal
sympathetic nerve activity (SNA).[11] Ghrelin can also act
directly on the central nervous system (CNS) and alter the
sensitivity of CNS to other hormones participating in regulation
of sympathetic activity.[12] Administration of ghrelin brings
down the plasma levels of epinephrine and dopamine and shifts
the balance of autonomic nervous activity toward
parasympathetic nervous activity.[11]
Ghrelin increases the size of cardiomyocytes, prolongs their
survival, and protects the cardiomyocytes against apoptosis and
myocardial injury induced by endoplasmic reticulum stress
(ERS) through a GHS-R1a, calmodulin-dependent protein
kinase kinase (CaMKK), and adenosine monophosphate (AMP)-
activated protein kinase (AMPK) pathway.[13] Administration
of ghrelin lowers the release of lactate dehydrogenase (LDH)
and myoglobin by the cardiomyocytes, indicating protection
against cardiomyocyte injury. So also, ghrelin may have other
cardiovascular beneficial effects in the form of prevention of
atherosclerosis as well as protection from ischemia and
reperfusion injury.
Levels of Angiotensin II (Ang II) and ghrelin are both
significantly increased in patients with HF.[14] Ghrelin inhibits
cardiomyocyte apoptosis both in vivo and in vitro. Ghrelin
inhibits the Ang II induced cardiomyocyte apoptosis in patients
with HF. Ghrelin also inhibits the AT1 receptor up-regulation
induced by Ang II, thereby playing a role in preventing HF.[14]
Elevated levels of ghrelin in patients with HF can be a
protective compensatory mechanism for reduced body weight in
order to enhance appetite and weight gain in cachexia patients
with HF. However, Chang et al. has reported that plasma ghrelin
levels are significantly lower in patients with HF and also differ
with the severity of HF and that higher levels of ghrelin is an
indicator of a better prognosis for HF.[15] Thus; ghrelin can be
considered as a new biomarker of severity as well as prognostic
predictor for patients with CHF.
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CONCLUSION
The multifunctional nature of ghrelin makes it an interesting
pharmacological target for various diseases. Future researches
are needed to evaluate the efficacy of ghrelin as a new
biomarker and prognostic tool and for exploring its therapeutic
potential in patients suffering from CHF.
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Footnotes
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Source of Support: Nil

Conflict of Interest: None declared.

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