Parkin Moderates Hypertrophy and Heart Failure Following Cardiac Pressure Overload


Eileen Gonzalez , Dieter Kubli, Nicole Purcell


├ůsa Gustafsson, Associate Professor of Pharmacology, University of California, San Diego

First discovered for its loss-of-function in the brain during Parkinson’s disease, the E3 ubiquitin ligase Parkin has been identified as an important regulator of mitochondrial autophagy (mitophagy) by selectively marking damaged mitochondria for removal. We previously found that Parkin plays an essential role in clearing dysfunctional mitochondria after myocardial infarction (MI), and mice deficient in Parkin (Parkin-/-) have increased injury and mortality after MI. However, it is currently unknown if Parkin also plays a role in adapting to hemodynamic stress. Here, we investigated the functional importance of Parkin in pathological cardiac hypertrophy. Wild type (WT), Parkin-/-, and cardiac-specific Parkin transgenic (Parkin-TG) mice were subjected to trans-aortic constriction (TAC). Compared to WT mice, Parkin-/- mice failed to develop cardiac hypertrophy in response to TAC. While WT mice showed increased heart weight/tibia length, myocyte size, and upregulation of hypertrophy markers ANF, skeletal muscle actin, and Beta-myosin heavy chain (MHC-Beta) two weeks post-TAC, Parkin-/- mice did not. Parkin-/- hearts did have a blunted hypertrophic response, but cardiac function was still preserved. In contrast, Parkin-TG mice had an exacerbated hypertrophy response compared to WT mice. Parkin-TG mice had increased expression of MHC-Beta, significantly lower % Fractional Shortening and % Ejection Fraction than WT, and had developed pulmonary edema at this time, indicative of accelerated progression to heart failure. Our data suggest that overexpression of Parkin may lead to excessive clearance of mitochondria via mitophagy and increased susceptibility to heart failure in response to hemodynamic stress. However, lack of Parkin results in a failure to activate hypertrophy in response to hemodynamic stress, suggesting that Parkin plays a critical role in the hypertrophy response. This study demonstrates that the functional role of Parkin differs depending on the stress stimulus and advances our understanding of Parkin in the heart and its role in cardiovascular disease.

Presented by:

Eileen Gonzalez


Saturday, November 23, 2013


1:40 PM — 1:55 PM


Science 104

Presentation Type:

Oral Presentation