Abstract
Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [125I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (KD = 0.12 nM, human; KD = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.
Highlights
The pairing of the kisspeptin receptor encoded by the KISS1R gene, with its cognate ligand, kisspeptin, in 2001 [2,3,4] led to a number of discoveries regarding the physiological functions of this system
Expression of kisspeptin receptor mRNA was identified in samples of human isolated cardiomyocytes (Figure 1B) confirming the potential of human heart tissue to express kisspeptin receptor protein
In sections of human heart kisspeptin receptor-like immunoreactivity (2LI) was detected in myocardium from all regions of explanted hearts investigated and in sections of atrial appendage obtained from coronary artery bypass graft operations
Summary
The pairing of the kisspeptin receptor (originally named GPR54, [1]) encoded by the KISS1R gene, with its cognate ligand, kisspeptin, in 2001 [2,3,4] led to a number of discoveries regarding the physiological functions of this system. KP-54 is cleaved from a single precursor, encoded by the KISS1 gene, and smaller fragments of kisspeptin have been identified that are cleaved from KP-54 by unidentified proteases. These fragments, KP-14, KP-13 and KP-10, retain biological activity [3], suggesting that some or all of the C-terminal ten amino acids are essential for receptor activation. Kisspeptins are able to down-regulate MMPs, at both the transcriptional [29] and protein [30] levels. This may represent different levels/points of regulatory feedback under various circumstances, for instance in the different stages of pregnancy or in pathological states
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