Cardiac oxidative stress and dysfunction by fine concentrated ambient particles (CAPs) are mediated by angiotensin-II

Abstract

Inhalation exposure to fine concentrated ambient particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine particulate matter (PM) exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin-converting enzyme (ACE) inhibitor (benazepril), or an angiotensin receptor blocker (ARB; valsartan) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard fine particle concentrator (fine PM mass concentration: 440 +/- 80 microg/m(3)). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, thiobarbituric acid reactive substances (TBARS) and for plasma levels of angiotensin-II. Also, continuous electrocardiogram (ECG) measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pre-treatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARS), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events.

Fig. 1. Angiotensin-II plasma levels in rats exposed to fine PM

Adult Sprague Dawley rats treated with saline, Benazepril or Valsartan were exposed to fine PM or filtered air for 5 hours in the HFPC. Blood samples were collected at the end of the exposure and processed for the determination of angiotensin-II in plasma, as described in the Methods section. Bars represent the mean value of 4-5 independent experiments. * p <0.002 vs. control. † p< 0.05 vs. PM.

Fig. 2. Inhibition of Angiotensin-II production prevents cardiac oxidative stress by fine PM

Adult Sprague Dawley rats were given 0.5 mL of either saline of 10mg/mL Benazepril via gavage 3 consecutive days before the exposure to fine PMor filtered air. At the end of the 5-hours exposure rats were immediately assessed for heart CL (A) * p <0.006 vs. control or Benazepril . † p< 0.006 vs. PM. After CL determination, the hearts were excised and processed for TBARS (B) as described in the Methods section. * p <0.03 vs control or Benazepril . Values represent the mean of 6-8 independent experiments ± SEM.

Fig. 2. Inhibition of Angiotensin-II production prevents cardiac oxidative stress by fine PM

Adult Sprague Dawley rats were given 0.5 mL of either saline of 10mg/mL Benazepril via gavage 3 consecutive days before the exposure to fine PMor filtered air. At the end of the 5-hours exposure rats were immediately assessed for heart CL (A) * p <0.006 vs. control or Benazepril . † p< 0.006 vs. PM. After CL determination, the hearts were excised and processed for TBARS (B) as described in the Methods section. * p <0.03 vs control or Benazepril . Values represent the mean of 6-8 independent experiments ± SEM.

Fig. 3. Inhibition of Angiotensin-II binding prevents cardiac oxidative stress by fine PM

Adult Sprague Dawley rats were given 0.5 mL of either saline or 40mg/mL Valsartan 2 hours prior to exposure to fine PM or filtered air. At the end of the 5-hours exposure rats were immediately assessed for heart CL (A) * p <0.003 vs. control or Valsartan . † p< 0.003 vs. PM. After CL determination, the hearts were excised and processed for TBARS (B) as described in the Methods section. *p <0.002 vs. control or Valsartan . † p< 0.008 vs. CAPs Values represent the mean of 8-10 independent experiments ± SEM.

Fig. 3. Inhibition of Angiotensin-II binding prevents cardiac oxidative stress by fine PM

Adult Sprague Dawley rats were given 0.5 mL of either saline or 40mg/mL Valsartan 2 hours prior to exposure to fine PM or filtered air. At the end of the 5-hours exposure rats were immediately assessed for heart CL (A) * p <0.003 vs. control or Valsartan . † p< 0.003 vs. PM. After CL determination, the hearts were excised and processed for TBARS (B) as described in the Methods section. *p <0.002 vs. control or Valsartan . † p< 0.008 vs. CAPs Values represent the mean of 8-10 independent experiments ± SEM.

Fig. 4

Schematic representation of the possible mechanism(s) connecting PM exposure, increases in Angiotensin-II blood levels, and cardiac alterations. PM: particulate matter; ROS: reactive oxygen species; TRP receptors: Transient Receptor Potential receptors.