Endogenous Ghrelin Attenuates Pressure Overload–Induced Cardiac Hypertrophy via a Cholinergic Anti-Inflammatory Pathway

Abstract

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin’s ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1β and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload–induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.

Ghrelin and hormonal markers under exercise training in patients with heart failure with preserved ejection fraction: results from the Ex‐DHF pilot study

“…We interpret the currently observed increase in endogenous ghrelin levels under ET to be consistent with the alterations observed in studies in older adults18 but consider it to may have additional clinical consequences in the setting of HF. Animal data suggest that endogenous ghrelin plays a crucial role in attenuating pressure overload‐induced cardiac hypertrophy and diastolic dysfunction 21. Mao et al 21.…”

“…discuss these effects because of the activation of a cholinergic anti‐inflammatory pathway. By simultaneously evoking sympathetic inhibition and parasympathetic activation, ghrelin is considered to be effective against cardiovascular diseases 21. Given that ghrelin was found to inhibit apoptosis of cardiomyocytes and endothelial cells in vitro ,15 it decreases blood pressure and increases cardiac output 16.…”

The differences in the relationship between diastolic dysfunction, selected biomarkers and collagen turn-over in heart failure patients with preserved and reduced ejection fraction

“…This may be caused by the fact that relaxation induced by ghrelin was decreased by inhibition of prostaglandins release and exacerbated by nitric oxide synthase inhibition [30]. Furthermore, the higher level of ghrelin in patients with HFrEF may have a cardioprotective effect because ghrelin attenuates pressure overload induced by cardiac hypertrophy via a cholinergic anti-inflammatory pathway and decreases deposition of collagen in the heart muscle [31,32].…”

Pressure Overload, Sympathetic Drive, and Inflammation

“…As the authors nicely summarize "Endogenous ghrelin plays a crucial role in … cardiac hypertrophy, and this likely occurs through the activation of the cholinergic anti-inflammatory pathway." 3 Furthermore, the finding cannot explain the positive relationship between excessive ghrelin and cardiac hypertrophy index in patients. 7 In general, there are problems to translate these findings into clinical practice.…”

“…The concept that ghrelin via inhibition of inflammation attenuates cardiac hypertrophy also requires that inflammation contributes to hypertrophy and its transition to heart failure. As a read-out for inflammation, the authors used interleukin-6 concentration in their study, 3 but interleukin-6 itself can improve cardiac function, leading us to questions that still remain. 6 The presented study does not really rule out the possibility that acetylcholine and ghrelin attenuate hypertrophy by acting directly on cardiomyocytes.…”