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Review
. 2022 Apr 7;23(8):4103.
doi: 10.3390/ijms23084103.

Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy

David Aluja  1 , Sara Delgado-Tomás  1 , Marisol Ruiz-Meana  1   2 , José A Barrabés  1   2 , Javier Inserte  1   2
Affiliations
Review

Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy

David Aluja et al. Int J Mol Sci. .

Abstract

Despite advances in its treatment, heart failure remains a major cause of morbidity and mortality, evidencing an urgent need for novel mechanism-based targets and strategies. Myocardial hypertrophy, caused by a wide variety of chronic stress stimuli, represents an independent risk factor for the development of heart failure, and its prevention constitutes a clinical objective. Recent studies performed in preclinical animal models support the contribution of the Ca2+-dependent cysteine proteases calpains in regulating the hypertrophic process and highlight the feasibility of their long-term inhibition as a pharmacological strategy. In this review, we discuss the existing evidence implicating calpains in the development of cardiac hypertrophy, as well as the latest advances in unraveling the underlying mechanisms. Finally, we provide an updated overview of calpain inhibitors that have been explored in preclinical models of cardiac hypertrophy and the progress made in developing new compounds that may serve for testing the efficacy of calpain inhibition in the treatment of pathological cardiac hypertrophy.

Keywords: calpain; calpastatin; heart failure; myocardial hypertrophy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram showing the main proposed mechanisms by which calpains promote cardiac hypertrophy. Red crosses indicate calpain substrates that are involved in hypertrophic signaling pathways. From left to right: Calpain-2-dependent proteolysis of JPH2 generates a JPH2-CT fragment that translocates to the nucleus and favors hypertrophy. Calpain-1-dependent proteolysis of JPH2 produces a JPH2-NT fragment that acts as a stress-adaptive transcription regulator preventing hypertrophy. Calpain-dependent degradation of IkBα activates NFκB. Calpain activity promotes the upregulation of GRK2 by mechanisms affecting both its stability (degradation of MDM2) and transcription (activation of NFκB). GRK2 overexpression phosphorylates IκBα promoting its proteosomal degradation and the subsequent activation of NFκB. Proteolysis of cain/cabin or calcineurin AID induces the activation of NFAT. AID, autoinhibitory domain; JPH2, junctophilin 2; JPH2-CT, junctophilin 2 C-terminal fragment; JPH2-NT; SR, sarcoplasmic reticulum.
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