Evidence for a role of mast cells in the evolution to congestive heart failure

Abstract

Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/W(v)) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/W(v) and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W(v) mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.

Figure 1.

Microscopic analysis at 15 wk after aortic banding. (A) Relative area of fibrosis. Values are mean ± SEM. *P < 0.05 vs. W/W^v mice and sham operated mice. (B) Histological staining of left ventricular fibrosis (Sirius red). Perivascular collagen accumulation (red) is more prominent in WT hypertensive mouse. Original magnification, ×200. +, banded mice; −, sham-operated mice. (C) Transmission electron microscopy. In WT mice (left panel), clusters of mitochondria (mit) of various shape and size were noted. A decrease in the density of myofibrils is also apparent. Original magnification, ×5,000. Bar, 5 μm.

Figure 1.

Microscopic analysis at 15 wk after aortic banding. (A) Relative area of fibrosis. Values are mean ± SEM. *P < 0.05 vs. W/W^v mice and sham operated mice. (B) Histological staining of left ventricular fibrosis (Sirius red). Perivascular collagen accumulation (red) is more prominent in WT hypertensive mouse. Original magnification, ×200. +, banded mice; −, sham-operated mice. (C) Transmission electron microscopy. In WT mice (left panel), clusters of mitochondria (mit) of various shape and size were noted. A decrease in the density of myofibrils is also apparent. Original magnification, ×5,000. Bar, 5 μm.

Figure 1.

Microscopic analysis at 15 wk after aortic banding. (A) Relative area of fibrosis. Values are mean ± SEM. *P < 0.05 vs. W/W^v mice and sham operated mice. (B) Histological staining of left ventricular fibrosis (Sirius red). Perivascular collagen accumulation (red) is more prominent in WT hypertensive mouse. Original magnification, ×200. +, banded mice; −, sham-operated mice. (C) Transmission electron microscopy. In WT mice (left panel), clusters of mitochondria (mit) of various shape and size were noted. A decrease in the density of myofibrils is also apparent. Original magnification, ×5,000. Bar, 5 μm.

Figure 2.

Real-time quantitative PCR analysis and angiotensin II concentrations in plasma. (A) mRNA levels of mMCP-5. (B) Angiotensin II concentrations in plasma. (C) mRNA levels of angiotensinogen in the hearts. (D) mRNA levels of ANP. +, banded mice; −, sham-operated mice. Values represent the normalized mean ± SEM. *P < 0.05.

Figure 2.

Real-time quantitative PCR analysis and angiotensin II concentrations in plasma. (A) mRNA levels of mMCP-5. (B) Angiotensin II concentrations in plasma. (C) mRNA levels of angiotensinogen in the hearts. (D) mRNA levels of ANP. +, banded mice; −, sham-operated mice. Values represent the normalized mean ± SEM. *P < 0.05.

Figure 3.

Effects of tranilast on blood pressure, heart weight and echocardiographic measurements. (A) Arterial blood pressure. (B) Heart weight (mg)/body weight (g) ratio. (C) Left ventricular percent fractional shortening (FS). (D) Left ventricular dimensions. Dd, enddiastolic diameter; Ds, endsystolic diameter. Values are mean ± SEM. *P < 0.05. +, banded mice; −, sham-operated mice.