Related Experiment Video
Updated: Jan 21, 2026
Isolation of Functional Cardiac Immune Cells
Published on: December 5, 2011
Regulation of Cardiac Mast Cell Maturation and Function by the Neurokinin-1 Receptor in the Fibrotic Heart
Alexander Widiapradja1,2, Edward J Manteufel3, Heather M Dehlin3
1Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
Insights
Substance P (SP) binding to neurokinin-1 receptors (NK-1R) promotes cardiac fibrosis by maturing mast cells (MCs). However, MC activation leading to fibrosis requires additional stimuli beyond NK-1R signaling.
Area of Science:
- Cardiovascular Biology
- Immunology
- Fibrosis Research
Background:
- Cardiac fibrosis, a key factor in diastolic dysfunction and heart failure, is linked to Substance P (SP) and neurokinin-1 receptor (NK-1R) activation.
- While SP-NK-1R signaling contributes to cardiac fibrosis in hypertension, direct fibroblast activation is not the primary mechanism.
- Mast cells (MCs) are implicated in cardiac fibrosis and respond to SP, suggesting a potential mediating role.
Purpose of the Study:
- To investigate the role of mast cells (MCs) in mediating the fibrotic effects of Substance P (SP) via neurokinin-1 receptor (NK-1R) signaling.
- To determine if NK-1R blockade affects mast cell maturation and subsequent cardiac fibrosis.
- To elucidate the necessity of mast cell NK-1Rs for SP-induced mast cell activation and fibrosis.
Main Methods:
- Treatment of spontaneously hypertensive rats (SHR) with an NK-1R antagonist (L732138) to assess effects on mast cell maturation.
- Utilizing angiotensin II-infused mice to examine the impact of NK-1R blockade on cardiac mast cell maturation.
- Employing MC-deficient mice, with and without MC reconstitution (including NK-1R deficient MCs), to evaluate the role of MCs and their NK-1Rs in angiotensin II-induced cardiac fibrosis.
Main Results:
- NK-1R blockade with L732138 prevented increased mast cell maturation in spontaneously hypertensive rats and angiotensin II-infused mice.
- MC-deficient mice did not develop fibrosis after angiotensin II infusion.
- Reconstitution of MC-deficient mice with wild-type or NK-1R-deficient MCs both led to fibrosis, indicating NK-1Rs are not required for MC activation in this context.
Conclusions:
- Neurokinin-1 receptor (NK-1R) activation promotes mast cell (MC) maturation.
- Mast cell (MC) activation leading to cardiac fibrosis is dependent on stimuli other than NK-1R signaling.
- Mast cells (MCs) mediate cardiac fibrosis, but their activation requires additional pathways beyond NK-1R stimulation.
Abstract:
Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.
More Related Videos
Related Concept Videos
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
01:31Regulation of Heart Rates
The SNS increases heart rate through the release of norepinephrine and epinephrine, which act on beta-1 adrenergic receptors in the heart. This action increases the rate of depolarization in the sinoatrial (SA) node, the heart's...
01:18Physiology of the Heart: The Cardiac Cycle
Diastole: The Relaxation Phase
During diastole, all four heart chambers relax. The atrioventricular (AV) valves open, and the semilunar valves close. This phase sees the lowest chamber pressures, promoting ventricular filling. Venous blood enters the heart through the...
01:19Cardiac Output I:Effect of Heart Rate on Cardiac Output
Cardiac output (CO) refers to the total amount of blood ejected by one of the ventricles in liters per minute (L/min). In a resting adult, CO ranges from 5 to 6 L/min, adjusting according to the body's metabolic requirements.
Effect of Heart Rate on Cardiac Output
Cardiac output adapts to metabolic demands during stress, physical activity, or illness. The autonomic nervous system regulates heart rate via the sinoatrial node. The parasympathetic nervous system decreases heart...
01:26Testosterone: Functions and Regulation
01:21Cardiac Catheterization II: Right Heart Catheterization