Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis

Abstract

Ventricular hypertrophy is an ominous escalation of hemodynamically stressful conditions such as hypertension and valve disease. The pathophysiology of hypertrophy is complex and multifactorial, as it touches on several cellular and molecular systems. Understanding the molecular background of cardiac hypertrophy is essential in order to protect the myocardium from pathological remodeling, or slow down the destined progression to heart failure and cardiomyopathy. In this review we highlight the most important molecular aspects of cardiac hypertrophic growth in light of the currently available published research data.

Figure 1

Diagrammatic representation of main intracellular signaling pathways regulating cardiac hypertrophy. Elevated calcium ion levels downstream of GPCRs, either through activation of voltage-gated calcium channels or from intracellular stores, is sensed by calmodulin, which activates calcineurin. Calcineurin in turn dephosphorylates NFAT transcription factor, leading to its nuclear translocation, where it activates gene transcription. ROS can contribute to hypertrophy by direct interaction with cellular proteins and subsequent changes in cellular contraction and/or induction of apoptosis, or by activation of NFκB-mediated gene transcription. Inflammatory stimuli can exacerbate the disease condition by inducing interstitial inflammatory cell infiltration and fibrosis. Stress signals can trigger the activation MAP kinase cascades, which activate a number of downstream targets such as JNK, finally leading to transcriptional activation. Growth hormones induced by physiological cues, such as exercise or pregnancy, bind to and activate downstream signaling of RTKs, which, on the other hand, leads to adaptive hypertrophic growth. GPCR – G-protein-coupled receptor; RTK – receptor tyrosine kinase; MAPKKs – mitogen-activated protein kinase kinases; ROS – reactive oxygen species; RyR – Ryanodine receptor; PI3K – phosphoinositide-3 kinase; JNK – c-Jun N-terminal kinase; NFκB – nuclear factor kappa B; PKC – protein kinase C; Cam – calmodulin; CnA – calcineurin A; CnB – calcineurin B; NFAT – nuclear factor of activated T-cell; Akt – protein kinase B (PKB); mTOR – mammalian target of rapamycin; LPS – lipopolysaccharide.