PKC and PKN in heart disease

Abstract

The protein kinase C (PKC) and closely related protein kinase N (PKN) families of serine/threonine protein kinases play crucial cellular roles. Both kinases belong to the AGC subfamily of protein kinases that also include the cAMP dependent protein kinase (PKA), protein kinase B (PKB/AKT), protein kinase G (PKG) and the ribosomal protein S6 kinase (S6K). Involvement of PKC family members in heart disease has been well documented over the years, as their activity and levels are mis-regulated in several pathological heart conditions, such as ischemia, diabetic cardiomyopathy, as well as hypertrophic or dilated cardiomyopathy. This review focuses on the regulation of PKCs and PKNs in different pathological heart conditions and on the influences that PKC/PKN activation has on several physiological processes. In addition, we discuss mechanisms by which PKCs and the closely related PKNs are activated and turned-off in hearts, how they regulate cardiac specific downstream targets and pathways, and how their inhibition by small molecules is explored as new therapeutic target to treat cardiomyopathies and heart failure.

Advanced glycation end products facilitate proliferation and reduce early apoptosis of cardiac microvascular endothelial cell via PKCβ signaling pathway: insight from diabetic cardiomyopathy

“…PKCα, β, ε, θ, and δ isoforms have been proposed to be involved in the development of diabetic cardiac hypertrophy (5,33,34). PKCα is the predominant member among the different PKC isozymes expressed in the cardiac tissue (35)(36)(37)(38). PKCα is increased in human cardiac pathology (36,39) and during the transition to heart failure (40).…”

Characterization of the novel cardiolipin binding regions identified on the protease and lipid activated PKC‐related kinase 1

“…Protein kinase C‐related kinase 1 (PRK1; also known as PKN or PAK1) is a trypsin or lipid activated kinase that acts as an effector downstream of RhoA or Rac1, the small GTP‐binding proteins that regulate the assembly of focal adhesion and actin stress fibers, in vivo . Other studies demonstrated that PRK1 was required for the survival of cardiac myocytes and guanosine‐mediated protection of neurons under stressed conditions .…”

Targeting Mitochondrial Fission-Fusion Imbalance in Heart Failure

“…Protein kinase C is a family of ubiquitous serine/threonine kinases subdivided into three groups, according to their biochemical properties: (1) conventional (or classic) PKCs (α, βI, βII, and γ), which are Ca 2+ -and lipid-dependent; (2) novel PKCs (δ, θ, ε, and η), which are Ca 2+ -independent; and (3) atypical PKCs (ζ, ι/λ), which are Ca 2+ -independent but activated by lipids (recently review by [21]). All these isozymes are expressed in cardiac cells including cardiomyocytes, fibroblasts, and mast cells [29].…”

“…Protein kinase is a class of enzymes that modify other proteins by chemically adding the terminal γ-phosphate group of adenosine triphosphate (ATP) to serine, threonine, or tyrosine residues, also known as phosphorylation [21]. Special attention has been given to the relationship between the protein kinase C (PKC) and cardiac dysfunction, including heart failure [21][22][23].…”

“…Protein kinase is a class of enzymes that modify other proteins by chemically adding the terminal γ-phosphate group of adenosine triphosphate (ATP) to serine, threonine, or tyrosine residues, also known as phosphorylation [21]. Special attention has been given to the relationship between the protein kinase C (PKC) and cardiac dysfunction, including heart failure [21][22][23]. Recent pre-clinical studies provide evidence that activation of PKCβII isozyme in the heart contributes to heart failure [24••, 25-27], and its effects are related to inhibition of mitofusin 1 (Mfn1), a GTPase responsible for regulating mitochondrial dynamics and bioenergetics [28••].…”