Fig. 4.

A: model of EX-induced adaptations of coronary smooth muscle (CSM) in normal subjects (boldface indicates those elements altered by EX). The left center illustrates decreased intracellular calcium concentration ([Ca²⁺]_i) response to selective agonists (e.g., endothelin), which produces a reduced Ca²⁺-dependent activation of contraction. This decreased [Ca²⁺]_i occurs despite an increased Ca²⁺-influx through L-type Ca²⁺ channels (Ca_v1.2), which is buffered by a non-sarcoplasmic reticulum (SR), non-Na⁺/Ca²⁺ exchanger mechanisms. Nuclear Ca²⁺ responses ([Ca²⁺]_n) are similarly reduced by EX, which may affect Ca²⁺-dependent transcription factors (CaTF, e.g., cAMP response element-binding protein and nuclear factor of activated T cell) and target gene expression. On the top right note that EX increases spontaneous, slow-Ca²⁺ release from the SR into the subsarcolemmal space ([Ca²⁺]_ss), which may contribute to the increased activation of large-conductance Ca²⁺-activated (BK) K⁺ channels by EX. In addition, K_v channels are also activated by EX. In arteriolar CSM, Ca²⁺-dependent PKC (e.g., PKCα) signaling enhances Ca_v1.2, leading to activation of contractile filaments and enhanced myogenic tone. Together, these changes result in an increase in the gain of the vasomotor contractile system and a more stable mature CSM phenotype. B: proposed model illustrating the manner in which EX may interact with proatherogenic factors, thereby decreasing lesion progression and/or stimulating lesion regression of atherosclerosis through regulation of CSM phenotype in coronary artery disease (CAD; gray, atherogenic effects). Proatherogenic factors (such as PDGF-BB, TNF-α, leptin) upregulate intermediate conductance Ca²⁺-activated K⁺ channels (K_Ca3.1, IK) and voltage-independent Ca²⁺ channels (e.g., TRP) while suppressing Ca_v1.2 and BK (K_Ca1.1) channels. CAD also disrupts SR Ca²⁺ release and extrusion and increases [Ca²⁺]_n. As shown on the right, this ion channel profile switch enhances CSM synthesis of fibronectin (FN) and collagen I (Col I), leading to a more proinflammatory matrix composition and synthesis of proliferative genes (PLF). EX adaptations described in A produce a stable, noninflammatory phenotype and increased expression of collagens III and IV (Col III, IV), producing a noninflammatory matrix. Note that there are a number of similarities and differences in the effects of EX on CSM in normal and diseased states. RyR, ryanodine receptor; ROK, Rho-associated protein kinase; SMX, smooth muscle-specific gene expression; Myo, myocardin; AP1, activator protein-1.