ABSTRACT
Hypertension (HTN) is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of Catestatin (CST), a bioactive cleavage product of the prohormone Chromogranin A (CgA). In mouse models, HTN symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with knockout (KO) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted, but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of pro-inflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone-marrow transfer showed that macrophages produce CST and that the anti-hypertensive effects of CST are mediated in part via CST’s immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in HTN by reducing macrophage inflammation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Addition of telemetric measurement of blood pressure, anti-inflammatory effects of CST on bone marrow derived macrophages and bone marrow transplanted mice, IKKb2 signaling, expression of CgA and CST in peritoneal macrophages, norepinephrine levels in heart and kidney, and systolic, diastolic, and mean arterial blood pressure after ganglionic blockade.
ABBREVIATIONS
- BMDM
- bone marrow-derived macrophage
- BP
- blood pressure
- BMT
- bone marrow transfer
- CCL
- C-C motif chemokine ligand
- CXC
- C-X-C motif chemokine ligand
- CDN
- chlodronate
- CgA
- chromogranin A
- CST
- catestatin
- EPI
- epinephrine
- HTN
- hypertension
- IFN
- interferon
- IL
- interleukin
- IPC
- ischemic preconditioning
- IR
- ischemia/reperfusion
- KO
- knockout
- LV
- left ventricular
- LVDP
- LV developed pressure
- LVEDP
- LV end diastolic pressure
- LVPWd
- LV posterior wall thickness
- MAP
- mean arterial pressure
- IVSd
- interventricular septum wall thickness
- NE
- norepinephrine
- SBP
- systolic blood pressure
- TEM
- transmission electron microscopy
- TNF
- tumor necrosis factor
- WT
- wild-type