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A review found smoking and second-hand smoke to be a global underlying cause of death as large as pollution, which in that analysis was the largest major underlying factor

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ET-1 reduces NO bioavailability and influences endothelial function directly by both reducing eNOS expression [64, 73] and activity, and by activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a superoxide producing enzyme located in vascular cells and inflammatory cells such as macrophages [2, 67, 84]

You can find the study in full here

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