Decreased Expression of Voltage- and Ca ²⁺ -Activated K ⁺ Channels in Coronary Smooth Muscle During Aging

Abstract

—Aging is the main risk factor for coronary artery disease. One characteristic of aging coronary arteries is their enhanced contractile responses to endothelial vasoconstricting factors, which increase the risk of coronary vasospasm in older people. Because large-conductance voltage- and Ca 2+ -activated K + channels (MaxiK) are key regulators of vascular tone, we explored the possibility that this class of channels is diminished with increasing age. Using site-directed antibodies recognizing the pore-forming α subunit and electrophysiological methods, we demonstrate that the number of MaxiK channels is dramatically diminished in aged coronary arteries from old F344 rats. Channel density was reduced from 52±9 channels/pF (3 months old) to 18±5 channels/pF (25 to 30 months old), which represents a 65% reduction in the older population. Pixel intensity of Western blots was also diminished by ≈50%. Moreover, the age-related decrease in the channel protein expression was also evident in humans, which showed ≈80% reduction in 61- to 70-year-old subjects compared with 3- to 18-year-old youngsters and ≈45% reduction compared with 19- to 56-year-old adults. In agreement with a reduction of MaxiK channel numbers in aging coronary arteries, old coronary arteries from F344 rats contract less effectively (≈70% reduction) than young coronary arteries when exposed to the MaxiK channel blocker iberiotoxin. The contraction studies indicate that under physiological conditions, MaxiK channels are tonically active, serving as a hyperpolarizing force that opposes contraction. Thus, reduced expression of MaxiK channels in aged coronary arteries would lead to a decreased vasodilating capacity and increased risk of coronary spasm and myocardial ischemia in older people.

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

“…24 In contrast in rat coronary smooth muscle, there is downregulation of the transcripts for both the a-and the b-subunits correlating with a decrease in the activity of the channels seen with patch clamping. 24,[28][29][30] This suggests that therapies addressing age-related changes in the activity of MaxiK may need to be tailored to a particular organ.…”

Effect of aging on calcium signaling in C57Bl6J mouse cerebral arteries

“…-dependent potassium channels [34] (Georgeon-Chartier, Morel, personal preliminary data), and basal NO level in endothelial cells [51]. Our results could help understand the effects of aging on cardiovascular pathological risks.…”

Hypercontractility and impaired sildenafil relaxations in the BKCachannel deletion model of erectile dysfunction

“…In vascular smooth muscle of aged rats (20,29) as well as of humans (38), the BK Ca channel ␣-and ␤ 1 -subunit expression is decreased. Correlated with this downregulation are increased risks of cardiovascular diseases such as coronary artery vasospasm, myocardial ischemia, and infarct (20,38).…”

“…Correlated with this downregulation are increased risks of cardiovascular diseases such as coronary artery vasospasm, myocardial ischemia, and infarct (20,38). Recently, gene therapy using the gene for the pore-forming BK Ca ␣-subunit (Kcnma or Slo1) has been shown to restore age-related erectile function in vivo in rats (23,25).…”