Exercise Training Reverses the Decreased Coronary Smooth Muscle Calcium Buffering Seen in Diabetic Dyslipidemia.

Coronary artery disease (CAD) is increased 3- to 6-fold in diabetes. It has been proposed that decreased myoplasmic calcium (Cam) regulation underlies the increase in CAD seen in diabetic dyslipidemia. In normal, ôhealthyö coronary smooth muscle (CSM) cells, calcium (Ca) influx is tightly coupled with sarco-endoplasmic reticulum (SR) Ca-ATPase (SERCA) activity, and sarcolemmal Ca extrusion mechanisms, to buffer Cam levels. In diabetic dyslipidemia, intracellular Ca levels are increased, yet Ca influx is decreased, suggesting that Cam buffering mechanisms are impaired. Exercise training (EX) increases SR Cam buffering. PURPOSE: To test whether EX increases CSM Cam buffering in diabetic dyslipidemia. METHODS: Male Yucatan swine were maintained for 20 weeks: control (C), alloxan-induced diabetes (D), high fat/high cholesterol fed (F), DF, and EX DF (DFX). Cells were dispersed from the right coronary artery and loaded with the Ca indicator, Fura-2. Cam measurements were made by digital imaging epifluorescence microscopy and assessed as the 340/380nm ratio of the Fura-2 emission. RESULTS: Basal Cam levels for DF were significantly (P < 0.05) increased over C. EX not only restored basal Cam to control levels, but also significantly decreased the DFX basal Cam below C. To assess whether the EX-induced changes were due to alterations in CSM Cam buffering capacity by SERCA, the SR was depleted with a 5mM caffeine, Ca-free (CAF) solution and then depolarized with a 2mM Ca, 80mM K+ (2Ca80K) solution to induce Ca influx. The 2Ca80K-induced time to half-maximum (t-max) response for D, F, and DF was increased above C, suggesting an increase in SERCA activity that was attenuated in DFX. This result was contradictory to that predicted from the basal Cam levels and suggested an increase in Cam buffering capacity in DF. However, since the 2Ca80K t-max can also indicate Ca-influx via voltage-gated Ca-channels, the time to half-minimum (t-min) for the CAF response was examined. The CAF t-min response allowed for the distinction between Cam buffering and Ca influx mechanisms, since the absence of Ca in the extracellular solution eliminated possible Ca influx. The CAF t-min response for DF was significantly increased above all groups suggesting that Ca handling mechanisms other than SERCA, i.e. sodium-Ca (NCX) and/or plasmalemmal Ca-ATPase (PMCA) are altered in diabetic dyslipidemia. CONCLUSION: These results demonstrate that the ability to buffer CSM Cam is decreased in F and DF (diabetic dyslipidemia) and that EX reverses that decrease. SUPPORT: NIH RR13223, HL62552.