PKC-α regulates cardiac contractility and propensity toward heart failure

Abstract

The protein kinase C (PKC) family of serine/threonine kinases functions downstream of nearly all membrane-associated signal transduction pathways. Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing Prkca are hypocontractile. Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively. Mechanistically, modulation of PKC-alpha activity affects dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 (SERCA-2) pump inhibitory protein phospholamban (PLB), and alters sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha directly phosphorylates protein phosphatase inhibitor-1 (I-1), altering the activity of protein phosphatase-1 (PP-1), which may account for the effects of PKC-alpha on PLB phosphorylation. Hypercontractility caused by Prkca deletion protects against heart failure induced by pressure overload, and against dilated cardiomyopathy induced by deleting the gene encoding muscle LIM protein (Csrp3). Deletion of Prkca also rescues cardiomyopathy associated with overexpression of PP-1. Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Calcineurin dephosphorylates the nuclear factor of activated T cells, which then translocates to the nucleus, interacts with the cardiac zinc finger transcription factor (GATA4),34 and orchestrates the reactivation of fetal genes such as natriuretic peptides and alpha‐skeletal muscle actin, which were increased in all phenotypes here. Calcineurin also activates protein kinase C,40 and activated protein kinase C in cardiac stress37 phosphorylates and inhibits inhibitor 1, leading to phospholamban dephosphorylation and inhibition of SERCA2a activity. Interestingly, despite enhanced expression of fetal genes in all phenotypes, p‐phospholamban, S16 was increased in the CR and MILD phenotypes and decreased in the MOD phenotype only.…”

The role of protein kinase C-mediated phosphorylation of sarcomeric proteins in the heart—detrimental or beneficial?

“…Interestingly, Molnar et al (2009) showed a significant increase in PKCα binding to the cardiomyofilament contractile proteins following application of Ca 2+ (Molnar et al 2009), indicating a role for PKCα-mediated phosphorylation on myofilament contractile function. Braz et al (2004) stated that PKCα is also localized in a weak sarcomeric pattern in unstimulated adult cardiac myocytes and that upon stimulation with phorbol myristate acetate, PKCα translocates to the Z-lines and the T-tubular network.…”

“…In transgenic mice over-expressing PKCα, Braz et al (2004) observed signs of cardiac hypertrophy at the age of 8 months. PKCα directly phosphorylated I-1 and thereby altered the activity of protein phosphatase-1 (PP-1).…”

“…PKCα directly phosphorylated I-1 and thereby altered the activity of protein phosphatase-1 (PP-1). Via this pathway, changes in PKCα activity might indirectly dephosphorylate phospholamban (PLB) and thereby alter SR Ca 2+ loading and the calcium transient (Braz et al 2004).…”

“…The regulatory role of PKC may be even larger during cardiac disease, as increased PKC activity and expression levels have been shown in the failing heart (Belin et al 2007;Braz et al 2004;Lamberts et al 2007). …”