Exposure to concentrated ambient particulate matter induces reversible increase of heart weight in spontaneously hypertensive rats

Abstract

Background: Exposure to ambient PM2.5 increases cardiovascular mortality and morbidity. To delineate the underlying biological mechanism, we investigated the time dependence of cardiovascular response to chronic exposure to concentrated ambient PM2.5 (CAP).

Methods: Spontaneously hypertensive rats (SHR) were exposed to CAP for 15 weeks, and blood pressure (BP), cardiac function and structure, and inflammations of lung, hypothalamus, and heart were measured at different time points.

Results: Chronic exposure to CAP significantly increased BP, and withdrawal from CAP exposure restored BP. Consistent with its BP effect, chronic exposure to CAP significantly decreased cardiac stroke volume and output in SHR, accompanied by increased heart weight and increased cardiac expression of hypertrophic markers ACTA1 and MYH7. Withdrawal from CAP exposure restored cardiac function, weight, and expression of hypertrophic markers, supporting the notion that cardiac dysfunction and hypertrophy is subsequent to hypertension. In agreement with the role of systemic inflammation in mediating the cardiovascular effects of CAP exposure, chronic exposure to CAP markedly increased expression of pro-inflammatory cytokines in lung, heart, and hypothalamus. However, withdrawal from exposure resolves inflammation in the heart and hypothalamus, but not in the lung, suggesting that CAP exposure-induced systemic inflammation may be independent of pulmonary inflammation.

Conclusion: Chronic exposure to CAP induces reversible cardiac dysfunction and hypertrophy, which is likely to be subsequent to the elevation in BP and induction of systemic inflammation as evidenced by increased mRNA expression of pro-inflammatory cytokines in diverse tissues.

Fig. 1

Exposure to CAP induces reversible increase in blood pressure. a, Experimental design: SHR were exposed to CAP for 15 weeks. Blood pressure was measured weekly. Following echocardiography in week 20 and week 25, rats were euthanized for myography and tissue harvesting. b, the blood pressure response of SHR to repeated CAP exposure and subsequent withdrawal. *p < 0.05 vs FA, two way ANOVA. n = 12 or 6/group

Fig. 2

Exposure to CAP induces reversible vascular dysfunction. SHR were euthanized shortly after 15 weeks of exposure to CAP (a–c, week 20) or 5 weeks of withdrawal from CAP exposure (d–f, week 25). Thoracic aorta were harvested and mounted to myography as described in Methods. The responses of isolated thoracic aorta to the indicated concentration of phenylephrine (PE, a and d), acetylcholine (Ach, b and d), and U-46619 (c and f) were analyzed, and results are presented as mean ± SEM. *p < 0.05 vs FA, two way ANOVA. n = 6/group

Fig. 3

Exposure to CAP induces reversible cardiac dysfunction. SHR were subjected to echocardiography shortly after 15 weeks of exposure to CAP (a and b, week 20) or 5 weeks of withdrawal from CAP exposure (C and D, week 25). Stroke volume (a and c) and cardiac output (b and d) are presented. *p < 0.05 vs FA, student’s t test. n = 6/group

Fig. 4

Exposure to CAP induces reversible cardiac dysfunction. a, the ratio of heart weight to body weight of SHR after 15 weeks of exposure to CAP (week 20). *p < 0.05 vs FA, student’s t test. n = 6/group. b and c, the cardiac protein levels of hypertrophic markers, ACTA1, MYH7, and SERCA2 after 15 weeks of exposure to CAP (week 20), as analysed by western blot. Representative images (b) and the summary (c) are presented. *p < 0.05 vs FA, one way ANOVA. D, the ratio of heart weight to body weight of SHR 5 weeks of withdrawal from CAP exposure (week 25). *p < 0.05 vs FA, student’s t test. n = 6/group. d and e, the cardiac protein levels of hypertrophic markers, ACTA1, MYH7, and SERCA2 5 weeks of withdrawal from CAP exposure (week 25), as analysed by western blot. Representative images (d) and the summary (e) are presented. *p < 0.05 vs FA, one way ANOVA

Fig. 5

Exposure to CAP induces reversible local and systemic inflammations. SHR were euthanized shortly after 15 weeks of exposure to CAP (a–c, week 20) or 5 weeks of withdrawal from CAP exposure (d–f, week 25). The mRNA expression levels of indicated pro-inflammatory cytokines in lung (a and d), hypothalamus (b and e), and heart (c and f) were assessed by real-time RT-PCR. *p < 0.05 vs FA, one way ANOVA. n = 6/group