Author + information
- Received August 10, 2018
- Revision received August 10, 2018
- Accepted August 10, 2018
- Published online February 25, 2019.
- Prachi Umbarkar, PhDa,
- Anand P. Singh, PhDa,
- Manisha Gupte, PhDa,
- Vipin K. Verma, PhDa,
- Cristi L. Galindo, PhDa,
- Yuanjun Guo, MDa,b,
- Qinkun Zhang, MDa,
- James W. McNamara, PhDc,
- Thomas Force, MDa and
- Hind Lal, PhDa,∗ ()
- aDivision of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- bDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee
- cDivision of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio
- ↵∗Address for correspondence:
Dr. Hind Lal, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB#348A, Nashville, Tennessee 37232.
• SMAD4 is the central intracellular mediator of TGF-β pathway.
• CM-specific loss of SMAD4 causes cardiac dysfunction independent of fibrotic remodeling.
• Deletion CM-SMAD4 affects CM survival.
• CM-SMAD4 loss leads to down-regulation of several ion channels’ genes, resulting in cardiac conduction abnormalities.
• CM-SMAD4 deletion alters sarcomere shortening kinetics, in parallel with reduction in cardiac myosin-binding protein C levels.
• These results demonstrate a fundamental role for CM-SMAD4–dependent TGF-β signaling in adult heart homeostasis.
The role of the transforming growth factor (TGF)-β pathway in myocardial fibrosis is well recognized. However, the precise role of this signaling axis in cardiomyocyte (CM) biology is not defined. In TGF-β signaling, SMAD4 acts as the central intracellular mediator. To investigate the role of TGF-β signaling in CM biology, the authors deleted SMAD4 in adult mouse CMs. We demonstrate that CM-SMAD4–dependent TGF-β signaling is critical for maintaining cardiac function, sarcomere kinetics, ion-channel gene expression, and cardiomyocyte survival. Thus, our findings raise a significant concern regarding the therapeutic approaches that rely on systemic inhibition of the TGF-β pathway for the management of myocardial fibrosis.
This work was supported by research grants to Dr. Lal from the National Heart, Lung, and Blood Institute (R01HL133290, R01HL119234) and American Heart Association (13SDG16930103). Dr. Galindo was supported by research grant (K01HL121045). Dr. Gupte was supported by Training Grant in Cardiovascular Research (T32 HL007411) from the National Heart, Lung, and Blood Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 10, 2018.
- Revision received August 10, 2018.
- Accepted August 10, 2018.
- 2019 The Authors