Calcium-calmodulin signaling elicits mitochondrial dysfunction and the release of cytochrome c during cadmium-induced apoptosis in primary osteoblasts

Toxicol Lett. 2014 Jan 3;224(1):1-6. doi: 10.1016/j.toxlet.2013.10.009. Epub 2013 Oct 19.

Abstract

Cadmium (Cd) is a toxic heavy metal used in industry and is associated with adverse effects on human health following long- or short-term environmental exposure. Although Cd is known to induce apoptosis in many human organ systems, the mechanism that underlies its toxicity in primary osteoblasts (OBs) is not yet established. In the present study, we confirmed that Cd induced apoptosis in OBs isolated from the craniums of fetal Sprague-Dawley rats. We then showed that exposure to Cd transiently increased intracellular calcium ([Ca(2+)]i) levels for up to 1.5h, after which the levels returned to normal. Pretreatment with the calcium chelator BAPTA-AM was able to prevent Cd-induced apoptosis by reversing Cd-induced changes in the mitochondrial transmembrane potential (ΔΨm). In addition, we found that the antagonist of calcium-dependent calmodulin (CaM), W-7, inhibited the conformational change of calmodulin induced by Cd. Furthermore, Cd-induced apoptosis could be inhibited by W-7 through the suppression of the mitochondrial release of cytochrome c to the cytosol and the reversal of Cd-activation of caspase-3. These data indicate that activated Ca(2+)/CaM might transmit apoptotic signals to the mitochondria during Cd-induced apoptosis. Our findings provide new insights into the mechanisms underlying apoptosis in OBs following exposure to Cd.

Keywords: Apoptosis; Cadmium; Calcium; Calmodulin; Cytochrome c; Osteoblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cadmium / toxicity*
  • Calcium / metabolism
  • Calcium Signaling / physiology*
  • Calmodulin / physiology
  • Cells, Cultured
  • Cytochromes c / metabolism*
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Mitochondria / physiology*
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology

Substances

  • Calmodulin
  • Sulfonamides
  • Cadmium
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • W 7
  • Cytochromes c
  • Calcium