Differential and conditional activation of PKC-isoforms dictates cardiac adaptation during physiological to pathological hypertrophy.

Abstract

A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week male Balb/c mice (Mus musculus) models, by reverse transcriptase-PCR, western blot analysis and M-mode echocardiography for cardiac function analysis. PKC-δ was significantly induced during pathological hypertrophy while PKC-α was exclusively activated during physiological hypertrophy in our study. PKC-δ activation during pathological hypertrophy resulted in cardiomyocyte apoptosis leading to compromised cardiac function and on the other hand, activation of PKC-α during physiological hypertrophy promoted cardiomyocyte growth but down regulated cellular apoptotic load resulting in improved cardiac function. Reversal in PKC-isoform with induced activation of PKC-δ and simultaneous inhibition of phospho-PKC-α resulted in an efficient myocardium to deteriorate considerably resulting in compromised cardiac function during physiological hypertrophy via augmentation of apoptotic and fibrotic load. This is the first report where PKC-α and -δ have been shown to play crucial role in cardiac adaptation during physiological and pathological hypertrophy respectively thereby rendering compromised cardiac function to an otherwise efficient heart by conditional reversal of their activation.

• Authors: Shaon Naskar, Kaberi Datta, Arkadeep Mitra, Kanchan Pathak, Ritwik Datta, Trisha Bansal, Sagartirtha Sarkar
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e104711 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25116170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Benzopyrans
• Protein Isoforms
• RNA, Small Interfering
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Collagen
• rottlerin
• Proto-Oncogene Proteins c-akt
• Protein Kinase C-alpha
• Protein Kinase C-delta
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Acetophenones (pharmacology)
• Adaptation, Physiological
• Animals
• Apoptosis (physiology)
• Benzopyrans (pharmacology)
• Cardiomegaly (pathology)
• Cells, Cultured
• Collagen (metabolism)
• Disease Models, Animal
• Down-Regulation
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (biosynthesis)
• Gene Expression Regulation
• Heart (physiopathology)
• Male
• Mice
• Mice, Inbred BALB C
• Muscle Cells (metabolism)
• Myocardium (metabolism)
• Phosphorylation
• Physical Conditioning, Animal
• Protein Isoforms (genetics, metabolism)
• Protein Kinase C-alpha (antagonists & inhibitors, metabolism)
• Protein Kinase C-delta (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (biosynthesis)
• RNA Interference
• RNA, Small Interfering
• STAT3 Transcription Factor (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)