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Published on: July 10, 2019
Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts
Sharon Etzion1, Raneen Hijaze2,3, Liad Segal2,4
1Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel. shar@bgu.ac.il.
Abstract:
Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of dilated cardiomyopathy and left ventricular non-compaction. These patients' primary fibroblasts exhibited abnormal lysosomal distribution and autophagy impairment. We therefore hypothesized that loss of PLEKHM2 impairs cardiac function via autophagy derangement. Here, we characterized the roles of Plekhm2 in the heart using global Plekhm2 knockout (PLK2-KO) mice and cultured cardiac cells. Compared to littermate controls (WT), young PLK2-KO mice exhibited no difference in heart function or autophagy markers but demonstrated higher basal AKT phosphorylation. Older PLK2-KO mice had body and heart growth retardation and increased LC3II protein levels. PLK2-KO mice were more vulnerable to fasting and, interestingly, impaired autophagy was noted in vitro, in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes. PLK2-KO hearts appeared to be less sensitive to pathological hypertrophy induced by angiotensin-II compared to WT. Our findings suggest a role of Plekhm2 in murine cardiac autophagy. Plekhm2 deficiency impaired autophagy in cardiofibroblasts, but the autophagy in cardiomyocytes is not critically dependent on Plekhm2. The absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage angiotensin-II-induced stress without detrimental consequences.
Insights
Plekhm2 protein deficiency impairs cardiac autophagy, particularly in cardiofibroblasts, affecting heart function in older mice. Compensatory mechanisms may protect against certain cardiac stresses.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Molecular Genetics
Background:
- Plekhm2 regulates endosomal trafficking and lysosomal distribution.
- Mutations in PLEKHM2 are linked to familial dilated cardiomyopathy and left ventricular non-compaction.
- Patient fibroblasts show impaired lysosomal distribution and autophagy.
Purpose of the Study:
- To investigate the role of Plekhm2 in cardiac function and autophagy using a mouse model.
- To determine if loss of Plekhm2 leads to cardiac dysfunction through autophagy derangement.
Main Methods:
- Generation and characterization of global Plekhm2 knockout (PLK2-KO) mice.
- Analysis of cardiac function, autophagy markers (e.g., LC3II), and AKT phosphorylation in wild-type (WT) and PLK2-KO mice.
- In vitro studies using Plekhm2-deficient cardiofibroblasts and cardiomyocytes.
- Assessment of response to angiotensin-II-induced pathological hypertrophy.
Main Results:
- Older PLK2-KO mice exhibited growth retardation and increased LC3II levels, suggesting impaired autophagy.
- Autophagy was impaired in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes.
- PLK2-KO mice showed increased vulnerability to fasting.
- PLK2-KO hearts were less sensitive to angiotensin-II-induced hypertrophy compared to WT hearts.
Conclusions:
- Plekhm2 plays a role in murine cardiac autophagy, particularly affecting cardiofibroblasts.
- Cardiac autophagy in cardiomyocytes is not critically dependent on Plekhm2.
- Plekhm2 deficiency may induce compensatory mechanisms that protect the heart against certain stresses like pathological hypertrophy.
