Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart

Abstract

Chronic activation of the sympathetic nervous system is a key component of cardiac hypertrophy and fibrosis. However, previous studies have provided evidence that also implicate inflammatory cells, including mast cells (MCs), in the development of cardiac fibrosis. The current study investigated the potential interaction of cardiac MCs with the sympathetic nervous system. Eight-week-old male spontaneously hypertensive rats were sympathectomized to establish the effect of the sympathetic nervous system on cardiac MC density, myocardial remodeling, and cytokine production in the hypertensive heart. Age-matched Wistar Kyoto rats served as controls. Cardiac fibrosis and hypertension were significantly attenuated and left ventricular mass normalized, whereas cardiac MC density was markedly increased in sympathectomized spontaneously hypertensive rats. Sympathectomy normalized myocardial levels of interferon-gamma, interleukin 6, and interleukin 10, but had no effect on interleukin 4. The effects of norepinephrine and substance P on isolated cardiac MC activation were investigated as potential mechanisms of interaction between the two. Only substance P elicited MC degranulation. Substance P was also shown to induce the production of angiotensin II by a mixed population of isolated cardiac inflammatory cells, including MCs, lymphocytes, and macrophages. These results demonstrate the ability of neuropeptides to regulate inflammatory cell function, providing a potential mechanism by which the sympathetic nervous system and afferent nerves may interact with inflammatory cells in the hypertensive heart.

Figure 1

Left ventricular collagen volume fraction in WKY (n=4), SHR (n=4), WKY+Symp (n=4) and SHR+Symp (n=4). All values are mean ± SEM. * = p<0.05 versus WKY; † = p<0.05 versus SHR.

Figure 2

Changes in left ventricular MC density in WKY (n=4), SHR (n=6), WKY+Symp (n=6) and SHR+Symp (n=4). All values are mean ± SD. * = p<0.05 versus WKY; † = p<0.05 versus SHR.

Figure 3

Changes in left ventricular levels of (A) IFN-γ, (B) IL-4, (C) IL-6 and (D) IL-10 in WKY (n=4), SHR (n=4), WKY+Symp (n=4) and SHR+Symp (n=4). All values are mean ± SEM. * = p<0.05 versus WKY; † = p<0.05 versus SHR.

Figure 4

Concentration-responses for histamine release by isolated cardiac MCs in response to norepinephrine (n=4) (A) and substance P (n=4) (B). Angiotensin II produced in response to stimulation with substance P (1 × 10^-4 M) by a mixed population of isolated cardiac inflammatory cells, including MCs, lymphocytes and macrophages (C). p<0.05 versus control.

Figure 5

Schematic depicting a possible series of events in the development of fibrosis in the hypertensive heart. Cardiac mast cell tryptase may activate protease activated receptor-2 (PAR-2) on afferent nerve fibers resulting in the release of substance P, which in turn acts on the neurokinin-1 (NK-1) receptor to induce production of angiotensin II by inflammatory cells. Angiotensin II, in addition to activating fibroblasts, may also stimulate efferent nerves to produce norepinephrine, in turn further stimulating fibroblasts to produce collagen.