Background

Aberrant Ca²⁺ handling is a prominent feature of heart failure. Elucidation of the molecular mechanisms responsible for aberrant Ca²⁺ handling is essential for the development of strategies to blunt pathological changes in calcium dynamics. The peptidyl-prolyl cis-trans isomerase peptidyl-prolyl isomerase 1 (Pin1) is a critical mediator of myocardial hypertrophy development and cardiac progenitor cell cycle. However, the influence of Pin1 on calcium cycling regulation has not been explored. On the basis of these findings, the aim of this study is to define Pin1 as a novel modulator of Ca²⁺ handling, with implications for improving myocardial contractility and potential for ameliorating development of heart failure.

Methods and results

Pin1 gene deletion or pharmacological inhibition delays cytosolic Ca²⁺ decay in isolated cardiomyocytes. Paradoxically, reduced Pin1 activity correlates with increased sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) and Na²⁺/Ca²⁺ exchanger 1 protein levels. However, SERCA2a ATPase activity and calcium reuptake were reduced in sarcoplasmic reticulum membranes isolated from Pin1-deficient hearts, suggesting that Pin1 influences SERCA2a function. SERCA2a and Na²⁺/Ca²⁺ exchanger 1 associated with Pin1, as revealed by proximity ligation assay in myocardial tissue sections, indicating that regulation of Ca²⁺ handling within cardiomyocytes is likely influenced through Pin1 interaction with SERCA2a and Na²⁺/Ca²⁺ exchanger 1 proteins.

Conclusions

Pin1 serves as a modulator of SERCA2a and Na²⁺/Ca²⁺ exchanger 1 Ca²⁺ handling proteins, with loss of function resulting in impaired cardiomyocyte relaxation, setting the stage for subsequent investigations to assess Pin1 dysregulation and modulation in the progression of heart failure.

Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+)-dependent metabolism during acute stress.