The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

Abstract

Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function.

Keywords: Air pollution; Autocrine/paracrine signaling; Cardiac dysfunction; Endothelin-1; Heart; Particulate matter.

Figure 1.

Schematic drawing of potential ET-1 production and function in the heart following PM exposure. ET-1 is released by both endocardial/myocapillary endothelial cells and cardiomyocytes and functions as an autocrine/paracrine signaling agent. ET-1 signaling affects the release of secondary autocrine/paracrine factors, such thromboxane A2 (TXA2), prostacyclin (PGI2), and NO. Changes in the concentrations of both primary and secondary autocrine/paracrine agents is likely important within the interstitium, though some changes can be observed in the circulation. Together, ET-1, increased TXA2, and reduced PGI2 and NO promote increased cardiac arrhythmias, positive cardiac inotropy, and positive cardiac chronotropy.