Abstract Body (Do not enter title and authors here): Background: The WHO estimates that air pollution causes 7 million premature deaths or about 1 in 8 global deaths. Epidemiological studies indicate that 60-70% of the premature mortality attributed to air pollution are cardiovascular deaths especially in those with pre-existing conditions such as hypertension and heart failure. The underlying pathophysiological mechanisms by which exposures to air pollution worsen cardiovascular disease are unclear.
Hypothesis: We hypothesized that the cardiovascular toxicity of particulate air pollution (PM_2.5) exposure would be enhanced in the setting of hypertension.
Methods: To test this, we combined air pollution exposure with a hypertension model (angiotensin II, 2.5 mg/kg bwt/day: ANGII osmotic pump) where normotensive and hypertensive male wildtype (WT, C57BL/6J) mice were exposed to filtered air or concentrated ambient PM_2.5 (CAP) for 3 weeks. To understand how combined hypertension and CAP exposure may alter cardiac remodeling, fibrosis and gene transcription (bulk RNAseq) were quantified.
Results: Mice with ANGII-infusion developed hypertension (non-invasive tail cuff) that was significantly elevated by CAP exposure. Hypertensive mice also developed cardiac hypertrophy (heart weight/tibia length ratio, mg/mm) independent of exposure [hypertensive: WT+Air, 9.6±0.4; WT+CAP, 10.3±0.4; normotensive groups: WT+Air, 8.3±0.3; WT+CAP, 7.4±0.1). CAP exposure had no effect on differential gene transcription in normotensive mice, yet CAP exposure significantly induced 996 differentially expressed genes (DEG) in hypertensive mice (332 up, 664 down). Gene Ontogeny (GO) analysis found dysregulated gene clusters (>40 genes) primarily for cardiac and striated muscle development and differentiation. Increased genes included caspase 12 (Casp12) and catechol-O-methyltransferase (Comt) genes that likely reflect enhanced apoptosis and sympathetic input. Downregulated genes included 2 collagen genes (Col5a3 and Col6a3) and death inducer-obliterator 1 (Dido1) -- reflecting dysregulated cardiac remodeling.
Conclusions: Hypertension enhanced the susceptibility of short-term air pollution exposure to worsen cardiovascular effects especially cardiac remodeling. This study reveals potential genetic mechanisms by which air pollution hastens cardiac dysregulation and promotes heart failure – a serious, globally relevant cardiovascular health risk of particulate air pollution.