Role of macrophage-specific calpain in hypercholesterolemia-induced atherosclerosis

  • Subramanian, Venkateswaran (PI)

Grants and Contracts Details


The objective of my proposal is to understand and elucidate the functional role of calpains in atherosclerosis development. Calpains are calcium-dependent cysteine proteases that are different from other proteases in calcium dependent activation and substrate binding specificity. Human atherosclerosis is associated with prolonged activation of calpains, however, surprisingly few cellular substrates of calpain have been identified in atherosclerosis. Recently, I have provided novel evidence that pharmacological inhibition of calpains attenuates atherosclerosis and NF-kB mediated inflammation in LDLr-/- mice. The two major isoforms, calpain-1 and -2, are ubiquitously expressed whereas others are tissue specific. Using calpain-1 deficient mice, I have determined that calpain-1 deficiency is associated with increased calpain-2 protein in atherosclerotic lesions and promotes atherosclerosis. This infers that calpain-2 compensates the loss of calpain-1 and both calpain-1 and -2 are involved in atherosclerosis development. Inactivation of calpain-2 gene results in early embryonic lethality in mice. Therefore, the role of calpain-1 and -2 in atherosclerosis development is presently unknown. Preliminary data demonstrated that: 1) immunostaining of atherosclerotic lesions revealed increased presence of calpain-1 and -2 protein, co-localized with macrophages 2) immunostaining of lesions from calpain-1 deficient mice showed increased presence of calpain-2 protein 3) calpain-1 and -2 protein are increased in lipid-loaded macrophages 4) calpain-1 or -2 overexpression promotes macrophage foam cell formation 5) Inhibition of calpain-1 and -2 by calpastatin overexpression prevents foam cell formation 6) calpain inhibition prevents NF-kB activation in macrophages. These results infer a novel role of calpains in atherosclerosis development. The availability of calpastatin overexpression transgenic mice provides an excellent model to study the role of calpains in atherosclerosis. Based on the background and preliminary data, my central hypothesis is that calpain deficiency in macrophages will attenuate hypercholesterolemia-induced atherosclerosis by suppressing macrophage foam cell formation and NF-kB mediated inflammation. To test this hypothesis, I will propose the following aims: Aim 1: Determine the role of calpain in macrophage foam cell formation and inflammation. Aim 2: Determine the contribution of macrophage specific-calpain to atherosclerosis
Effective start/end date1/1/1312/31/13


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