Calcium and diabetic vascular dysfunction: Focus on "Elevated Ca2+ sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells"

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Abstract

diabetes mellitus (dm) is characterized by hyperglycemia associated with either reduced insulin secretion (type I DM) or reduced target-cell insulin sensitivity (type II DM). The incidence of type II diabetes has risen sharply in Western countries in recent years—particularly in children and teenagers—as a result of lifestyle choices that promote obesity. Vascular dysfunction is a key phenotype of diabetes, and the resulting cardiovascular disease is the primary cause of death in individuals with diabetes (2, 9). Vascular dysfunction is responsible not only for increased risk of stroke and heart attack, but also for diabetic end-organ damage, including retinopathy, nephropathy, and neuropathy. Since vascular cells are the first to encounter the elevated levels of plasma glucose in diabetes, it follows that the vasculature is particularly vulnerable to diabetic injury. Hyperglycemia is associated with atherosclerosis, vascular calcification, and increased vascular tone in a variety of vascular beds (2). Barbagallo et al. (1) reported that glucose induces a concentration-dependent increase in global intracellular calcium concentration ([Ca2+]i) in cultured rat tail vascular smooth muscle (VSM) cells, and elevated cytosolic [Ca2+] has also been observed in diabetic rodent models (1, 14). The nature and characteristics of the Ca2+ signal responsible for the increase in [Ca2+]i in diabetes has not been determined; however, several lines of evidence have suggested that Ca2+ entry through L-type Ca2+ channels in VSM cell plasma membranes may play a role (11). Using total internal reflection fluorescence microscopy, Navedo et al. (11), in this issue, explored the relationship between exposure to high glucose (20 mM) and Ca2+ signaling in cerebral VSM cells, focusing on Ca2+ sparklets—elementary Ca2+ events reflecting Ca2+ entry through plasma membrane L-type voltage-dependent Ca2+ channels. Navedo et al. found that both low activity and high activity “persistent” Ca2+ sparklets are increased in cerebral VSM cells under voltage clamp in response to acute exposure to high glucose, as well as in cerebral VSM cells from diabetic mice. Additionally, Navedo et al. present evidence that acute stimulation of VSM cells with high glucose increases Ca2+ sparklet activity by increasing the number, but not the amplitude, of Ca2+ sparklets, and they further report that the increase in Ca2+ sparklets induced by high glucose occurs in specific locations in the VSM plasma membrane. Importantly, the authors show that the high glucose-induced increase in Ca2+ sparklet activity is dependent on targeting of cAMP-dependent protein kinase (PKA) to the membrane by A-kinase anchoring protein (AKAP) (Fig. 1). This mechanism is distinct from that by which angiotensin II (ANG II) stimulates an increase in VSM cell Ca2+ sparklet activity, which involves AKAP targeting of protein kinase C-α (PKCα), rather than PKA, to the membrane (12). Previous data indicated that PKCα is required for activation of persistent Ca2+ sparklets. However, this report provides the first evidence that persistent Ca2+ sparklet activity can be induced independently of PKCα. This report is also the first to describe a molecular mechanism by which hyperglycemia produces increased [Ca2+]i in VSM and suggests that this mechanism of Ca2+ sparklet activation may be uniquely initiated by hyperglycemia.

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