Calcium channel regulation in vascular smooth muscle cells: Synergistic effects of statins and calcium channel blockers

Abstract

In the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) we have reported a positive interaction between atorvastatin and amlodipine-based antihypertensive strategy in terms of the prevention of coronary events. In cellular and molecular studies on human vascular smooth muscle cells (VSMC) we have reported that transformation from a differentiated to a synthetic or dedifferentiated phenotype is associated with loss of function of L-type calcium channels and hence loss of potential responsiveness to calcium channel blockers (CCB). Statins directly inhibit cell cycle progression and dedifferentiation of VSMC due to their ability to inhibit the synthesis of isoprenoid cholesterol intermediates. We hypothesize that statins promote a more differentiated VSMC phenotype that results in upregulation of L-type calcium channels and restoration of a CCB-sensitive calcium influx pathway in VSMC, favourably affecting the balance that exists between VSMC proliferation, apoptosis and matrix metalloproteinase production with an associated increase in stability of atheromatous plaques.

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

“…7, dashed arrow). This leads to mitochondrial calcium influx and increased release of proapoptotic factors such as cytochrome c. Interestingly, it has been hypothesized by others that statins can directly increase the expression of L-type calcium channels in vascular smooth muscle cells (66). In our experimental paradigm, simvastatin did not alter total protein levels of L-or T-type channels.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…It is noteworthy that a synergism between statins and antihypertensive drugs has been observed in several clinical trials. Atorvastatin reduced primary events of CAD by 35% versus placebo group; this effect was augmented up to 53% in combination with the calcium channel blocker amlodipine (Clunn et al, 2010). In spontaneously hypertensive rats, quinapril administered in combination with atorvastatin lowered blood pressure, ameliorating cardiac and vessel function and hypertrophy, through increased rates of SMC apoptosis (Yang et al, 2005).…”

“…In spontaneously hypertensive rats, quinapril administered in combination with atorvastatin lowered blood pressure, ameliorating cardiac and vessel function and hypertrophy, through increased rates of SMC apoptosis (Yang et al, 2005). Moreover, statins, promoting the dedifferentiation of SMC, could up-regulate the expression of calcium channels, thereby reverting the loose of efficacy of calcium channel blockers that occurs with disease progression (Clunn et al, 2010). Simvastatin per se has been reported to block calcium entry through the inhibition of Rho/Rho kinase (Pérez-Guerrero et al, 2005).…”

Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats

“…They are used clinically to treat patients with cardiovascular disease like atherosclerosis, stroke and peripheral arterial disease due to their cholesterol lowering effect (Ali and Alexander, 2007;Golomb et al, 2008). However, statins exhibit umpteen pleiotropic cholesterol independent effects including anti-oxidants by reducing superoxide formation (Uekawa et al, 2014), anti-inflammatory by reducing macrophage migration , anti-microbial effect in staphylococcus blood infections (López-Cortés et al, 2013), modulation of the neurotrophic levels (Wu et al, 2008) and up-regulation of L-type Ca 2+ channel affecting smooth muscle contraction (Clunn et al, 2010). Due to these multiple activities, preclinical studies have suggested the potential beneficial role of statins in a number of other diseased states like cancer (Khurana et al, 2007;Kong et al, 2014;Mondul et al, 2011), arthritis (Gottschalk et al, 2014), chronic obstructive pulmonary disease (Criner et al, 2014), Alzheimer's disease and Parkinson's disease (Barone et al, 2014;Wolozin et al, 2007) and chronic kidney disease (Dasari et al, 2014).…”