Cellular and molecular effects of hyperglycemia on ion channels in vascular smooth muscle

Abstract

Diabetes affects millions of people worldwide. This devastating disease dramatically increases the risk of developing cardiovascular disorders. A hallmark metabolic abnormality in diabetes is hyperglycemia, which contributes to the pathogenesis of cardiovascular complications. These cardiovascular complications are, at least in part, related to hyperglycemia-induced molecular and cellular changes in the cells making up blood vessels. Whereas the mechanisms mediating endothelial dysfunction during hyperglycemia have been extensively examined, much less is known about how hyperglycemia impacts vascular smooth muscle function. Vascular smooth muscle function is exquisitely regulated by many ion channels, including several members of the potassium (K+) channel superfamily and voltage-gated L-type Ca2+ channels. Modulation of vascular smooth muscle ion channels function by hyperglycemia is emerging as a key contributor to vascular dysfunction in diabetes. In this review, we summarize the current understanding of how diabetic hyperglycemia modulates the activity of these ion channels in vascular smooth muscle. We examine underlying mechanisms, general properties, and physiological relevance in the context of myogenic tone and vascular reactivity.

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“… A-kinase anchor protein 7 isoform gamma (HLTLPF) modulates L-type Ca2+ channels [ 17 ]. Alterations of L-type Ca2+ channels may affect cardiac contraction [ 18 ], associate with diabetes [ 19 ] and can cause autism [ 20 ] and relate to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, neuropsychiatric diseases, and other CNS disorders [ 21 ]. Ataxin-2-like protein (QAIVSS) is involved in spinocerebellar ataxia type 2 [ 22 ], cutaneous T-cell lymphomas [ 23 ], is directly relevant to allergic disease [ 24 ], and its absence triggers mid-gestational embryonic lethality, affecting female animals more strongly [ 25 ].…”

“…A-kinase anchor protein 7 isoform gamma (HLTLPF) modulates L-type Ca2+ channels [ 17 ]. Alterations of L-type Ca2+ channels may affect cardiac contraction [ 18 ], associate with diabetes [ 19 ] and can cause autism [ 20 ] and relate to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, neuropsychiatric diseases, and other CNS disorders [ 21 ].…”

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“…Blocking K + and Ca 2+ channel can jointly or independently delay the action potential repolarization and intensify the blood vessel dilatation, and sometimes trigger irregular physiological responses in muscle and cardiovascular system [53,54]. However, this impeding effect has been often reported to play active roles in treating arrhythmia [55], hypoglycemia [56], and hyperglycemia [57], thus meaning GQDs could be potential ion channel antagonists to treat relevant diseases. Therefore, the inhibitory effects of GQDs on K + and Ca 2+ channel should be adequately evaluated by combing with other physiological responses.…”

The role of potassium in atherosclerosis

“…50 Another interesting role of potassium channels has been described in diabetic patients, where they are linked to both macro-and micro-vascular complications. 51 Kv channels are inhibited in hyperglycaemic states with consequent VSMC membrane depolarization and ultimately increased vasoconstriction 52 in experimental models. Also, a modulation in neurovascular coupling contributes to vasoconstriction in acute hyperglycaemic conditions.…”

“…This is not surprising as both ECs and VSCMs play a critical pathophysiological role in the vascular remodelling associated with hypertension 50 . Another interesting role of potassium channels has been described in diabetic patients, where they are linked to both macro‐ and micro‐vascular complications 51 . Kv channels are inhibited in hyperglycaemic states with consequent VSMC membrane depolarization and ultimately increased vasoconstriction 52 in experimental models.…”