Cadmium Modulates Expression of Vascular Alpha 1 Adrenoceptors and Aortic Smooth Muscle Cells Phenotype
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Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, including Qatar. Hypertension is one of the most common CVDs that contribute to this mortality. Cadmium (Cd) is a well-known pollutant that has been suggested to be a risk factor for hypertension. However, the underlying mechanisms are still lacking. Very little is known about the effect of Cd on the expression of vascular alpha-1 adrenoceptors (α1 ARs) in vascular smooth muscle cells (VSMCs). This study was therefore undertaken to determine the effect of Cd on the expression and sensitivity of vascular α1 ARs in vitro and in vivo. Along with that, there are several phenotypic changes could modulate the VSMCs function and contribute to CVDs including hypertension. These changes include hypertrophy, migration and senescence. The second objective of this study was to determine the effect of Cd on VSMCs phenotype. Human aortic smooth muscle cells (HASMCs) were incubated with different concentrations of cadmium chloride (CdCl2) for varying durations. The results indicated that Cd increases the expression of α1 ARs, cells were pre-incubated with actinomycin D, a DNA-dependent RNA synthesis inhibitor. Interestingly, the Cd-induced α1 ARs protein expression was abolished by actinomycin D. Moreover, this expression of α1 ARs was diminished when cells were pre-incubated with H89, a protein kinase A (PKA) inhibitor. This indicates that PKA plays an important role in mediating the Cd-induced expression of α1 ARs. α1 ARs activity was determined through functional study. Wistar rats were treated with CdCl2 at dose 15mg/kg/day via drinking water for 8 weeks. Blood pressure was measuredd at the baseline and after 30 days of treatment. Cd didn't affect the vascular reactivity of rat mesenteric arteries in response to α1 ARs agonists, phenylephrine and norepinephrine (NE) as well as blood pressure. Antagonizing α1 ARs with prazosin didn't show any response of other alpha's AR. To determine the effect of Cd on VSMCs phenotype, HASMCs were incubated with CdCl2. Our results showed that cadmium induces hypertrophy, migration and senescence. Taken together, our results dissect a novel pathway employed by Cd to increase expression (not the activity) of vascular α1 ARs, a major player in hypertension as well as VSMCs phenotypic modulation. This new paradigm offers a better understanding and thus potential amelioration of pollution-related CVDs.
- Biological & Environmental Sciences [16 items ]