Title:Catestatin: A Master Regulator of Cardiovascular Functions
Volume: 25
Issue: 11
关键词:
铬粒素A，肾上腺素能β-2受体，心肌病，心脏保护，心力衰竭，高血压，免疫细胞，烟碱-胆碱能受体。
摘要: Background: Cardiovascular disease (CVD), the most common cause of death
globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor
to morbidity and mortality from CVD.
Methods and Results: The plasma concentration of chromogranin A (CgA) is elevated in patients
with CVD as well as patients with established human essential hypertension and heart
failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished
in human essential hypertension. Low conversion of CgA-to-CST has been associated
with increased mortality in patients hospitalized with acute HF. Consistent with human
findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of
hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating
CST as a key player in regulating hypertension. In the peripheral system, CST decreases
blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or
causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate
variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla
(CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting
glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides
cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels,
and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement
(SAFE) pathways and consequent inhibition of mitochondrial permeability transition
pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of
Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction
in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for
a direct functional role of CST in the failing myocardium.
Conclusion: These multitude of effects establish CST as a master regulator of cardiovascular
functions.
