Acylated Ghrelin Protects Rat Hearts from Hyperthyroid-Induced Damage via Antioxidant and Anti-inflammatory Effects
Background
Hyperthyroidism, characterized by excessive thyroid hormone levels, often leads to significant cardiovascular complications, including cardiac hypertrophy (enlargement), dysfunction, and structural damage. The mechanisms involve increased metabolic rate, which elevates reactive oxygen species (ROS) and triggers inflammatory pathways. The cardiac renin-angiotensin system (RAS) is also implicated. Acylated ghrelin (AG), an endogenous peptide hormone, is known for its role in regulating growth hormone release and appetite, but it also possesses cardiovascular protective properties. This study investigates if AG can mitigate the cardiac damage induced by hyperthyroidism and explores the underlying antioxidant, anti-inflammatory, and RAS-modulating pathways involved.
Study Design
Male rats (n=12 per group) were divided into five groups: control, control + AG, l-thyroxin (l-Thy) to induce hyperthyroidism, l-Thy + AG, and l-Thy + AG + [D-Lys3]-GHRP-6 (a GHS-R1a antagonist). The study aimed to assess AG's protective effects on cardiac structure and function. Researchers measured cardiac weights, levels of reactive oxygen species, and various biomarkers of apoptosis, oxidative stress, and inflammation in the left ventricle tissue. Key endpoints included levels of caspase-3, cytochrome c, SOD2, GSH, TNF-α, and IL-6.
Results
L-thyroxin (l-Thy) administration significantly reduced endogenous levels of both acylated ghrelin (AG) and des-acyl ghrelin. Co-administering AG to l-Thy-treated rats successfully reduced cardiac weights and preserved left ventricular function and structure. AG treatment significantly increased protective factors like manganese superoxide dismutase (SOD2), total glutathione (GSH), and Bcl2. It also reduced markers of cellular damage and inflammation, including malondialdehyde, tumor necrosis factor-α (TNF-α), interleukin-6, and Bax, while decreasing the nuclear activity of NF-κB. Concurrently, AG downregulated components of the cardiac renin-angiotensin system.
A key finding was that the co-administration of the
GHS-R1aantagonist, [D-Lys3]-GHRP-6, completely prevented all the beneficial cardiac effects of AG in the hyperthyroid rats, confirming the receptor's critical role in this protective mechanism. AG also reduced the mRNA and protein levels ofNADPH oxidase 1, angiotensin II type 1 receptor (AT1R), andACE2.
Key Findings
- Acylated ghrelin (AG) reduced cardiac weights and preserved left ventricular function in rats with l-thyroxin-induced cardiac damage.
- AG increased levels of protective antioxidants
SOD2andGSHand the anti-apoptotic proteinBcl2in the heart. - AG administration decreased levels of inflammatory markers
TNF-αandinterleukin-6and reducedNF-κBactivity. - The protective effects of AG were entirely blocked by the
GHS-R1aantagonist [D-Lys3]-GHRP-6, confirming the receptor's essential role. - AG downregulated mRNA and protein levels of
NADPH oxidase 1, angiotensin II type 1 receptor, andACE2.
Why It Matters
This study highlights a potential therapeutic role for acylated ghrelin (AG) in mitigating the cardiovascular damage associated with hyperthyroidism. For individuals exploring peptide therapies, this suggests AG or GHS-R1a agonists could offer cardioprotective benefits, particularly in states of high metabolic stress. The findings underscore the importance of the GHS-R1a receptor pathway, indicating that simple ghrelin mimetics might not be effective if they don't properly engage this specific receptor. This research provides a rationale for investigating GHRPs or AG itself as an adjunct therapy to manage heart complications in hyperthyroid patients. However, this is an early-stage animal study, and clinical translation would require extensive human trials to establish safety, dosing, and efficacy. The paper does not provide a protocol for human use.
