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However, there have been new insights demonstrating that ONOO − is also involved in various signaling pathways, including a mechanism of vasodilation independent of cGMP.88 While NO clearly is an important signaling molecule, its overproduction has been implicated in various pathologies, including angiogenesis, mitochondrial dysfunction, and heart failure.89,90 “Nitrosative stress” may cause hyper-nitrosylation of various regulatory enzymes leading to dysregulation of several cellular and physiological processes including inhibition of autophagy.91 Moreover, hyperproduction of NO may also lead to upregulation of mammalian target of rapamycin (mTOR), the central regulating molecule of the major signaling pathways for cell metabolism, growth, proliferation, and survival.91 According to one theory of aging, the mTOR signaling pathway, driving developmental growth early in life, leads to age-related diseases through hyperfunction later in life.92 In fact, there is a growing list of physiological malfunctions linked to overstimulation of this NO-dependent signaling pathway, ranging from insulin resistance to neurodegenerative diseases to cancer, and even including hypertension itself
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