Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Heart Failure Pathogenesis

Background:

• Left ventricular hypertrophy (LVH) is a cardiac response to overload, potentially leading to heart failure.
• LVH can progress from concentric (cLVH) to eccentric (eLVH) types, resulting in pump failure.
• Endogenous molecular inhibitors of hypertrophy are recently identified targets.

Purpose of the Study:

• To compare myocardial mRNA expression of hypertrophy inhibitors in pressure-overload (cLVH) and volume-overload (eLVH) induced hypertrophy.
• To analyze the temporal expression of these inhibitors during the progression from cLVH to eLVH in a rat model.
• To investigate the pathophysiological significance of modified endogenous inhibitor expression in LVH.

Main Methods:

• Real-time PCR was used to quantify myocardial mRNA expression of hypertrophy inhibitors.
• Patient samples included pressure-overload induced cLVH (aortic stenosis) and volume-overload induced eLVH (mitral regurgitation).
• A rat model of pressure overload was used to study LVH progression from cLVH to eLVH.

Main Results:

• Each gene inhibitor exhibited a unique temporal expression profile during LVH progression.
• Changes in gene expression of negative regulators in rat models were mirrored in human cLVH and eLVH, except for SOCS-3.
• VDUP-1 and MCIP-1 expression was elevated in cLVH but normalized in eLVH in both rat and human subjects.

Conclusions:

• Expression levels of endogenous hypertrophy inhibitors are altered during LVH progression in both pressure and volume overload.
• Modified expression of these inhibitors, particularly MCIP-1 and VDUP-1, may play a significant role in the pathophysiology of heart failure.
• MCIP-1 (calcineurin inhibitor) and VDUP-1 (thioredoxin inhibitor) are identified as potential molecular switches in the progression of LV hypertrophy.