Cardiac myosin binding protein-C (cMyBP-C) is a heart-specific muscle protein that regulates cardiac structure and function. Mutations in the cMyBP-C gene are a leading cause of hypertrophic cardiomyopathy (HCM). Previously, we discovered and described a variant in the cMyBP-C gene (MYBPC3) that leads to a change in the C10 domain of the C'-region (cMyBP-C?C10) and is associated with the development of HCM and heart failure (HF). It has been estimated that cMyBP-C?C10 is inherited in ~60 million South Asians, who have a statistically higher risk of heart disease and higher mortality rate after myocardial infarction. However, the molecular mechanism underlying the pathogenicity of cMyBP-C?C10 is unknown. Therefore, our short-term goal is to define the pathogenic mechanism that leads to HCM via this genetic route and develop therapeutic strategies to treat it. Our long-term goal is to determine the molecular mechanisms underlying the pathophysiology of MYBPC3 mutations in relation to the etiology of HCM to provide a foundation for developing novel therapies. To those ends, the overall objectives are to (1) determine whether cMyBP-C?C10 plays a pathogenic role in the etiology of HCM by using a transgenic mouse model; (2) define whether activation of the protein kinase R-like ER kinase (PERK) pathway, one of the unfolded protein responses, is the molecular mechanism underlying cMyBP-C?C10 pathogenicity; and (3) determine whether expression of cMyBP-C?C10 further exacerbates ischemia-reperfusion injury and, if so, whether inhibition of the PERK pathway is cardioprotective. Our central hypothesis is that cMyBP-C?C10 causes HCM by inducing the PERK pathway, further aggravating IR injury and increasing morbidity and mortality. To test this hypothesis, a cardiac-specific transgenic mouse model expressing cMyBP-C?C10 in the heart has been established. It will be used to study the disease mechanism and to evaluate potential therapeutic targets. Pilot studies show that transgenic lines with 50% cMyBP-C?C10 expression, compared to endogenous cMyBP-C, show the HCM phenotype by 12 weeks of age, suggesting that cMyBP-C?C10 is sufficient to recapitulate the human HCM disease phenotype. Using these mice, SPECIFIC AIM 1 will precisely determine the pathological consequences of cMyBP-C?C10 on cellular and whole-organ function.
SPECIFIC AIM 2 will use pharmacologic and genetic approaches to determine whether inhibition of PERK can prevent and/or rescue the development of the HCM phenotype in cMyBP-C?C10 mice.
SPECIFIC AIM 3 will determine whether cMyBP-C?C10 expression is a risk factor for increased morbidity and mortality after IR injury. PERK inhibition will be tested for its ability to rescue the HCM phenotype and reduce the pathogenic consequences of IR injury.

Public Health Relevance

The long-term objective is to understand the pathogenesis of a MYBPC3 genetic variant known to cause hypertrophic cardiomyopathy (HCM) in approximately 60 million South Asian descendants. In particular, the proposed studies will determine the molecular mechanism underlying the pathogenicity of this mutation, leading to the discovery of cardioprotective agents to prevent or ameliorate HCM and heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130356-04
Application #
9612566
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
McNamara, James W; Grimes, Kelly M; Sadayappan, Sakthivel (2018) Basic Cardiovascular Sciences Scientific Sessions 2018. Circ Res 123:1024-1029
McNamara, James W; Sadayappan, Sakthivel (2018) Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology. Arch Biochem Biophys 660:121-128
Sadayappan, Sakthivel (2018) My Life, My Heart, and My(osin) Binding Protein-C. Circ Res 122:918-920
Viswanathan, Shiv Kumar; Puckelwartz, Megan J; Mehta, Ashish et al. (2018) Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3?25bpIntronic Deletion in South Asian Descendants. JAMA Cardiol 3:481-488
Lin, Brian Leei; Song, Taejeong; Sadayappan, Sakthivel (2017) Myofilaments: Movers and Rulers of the Sarcomere. Compr Physiol 7:675-692
Lynch 4th, Thomas L; Kuster, Diederik W D; Gonzalez, Beverly et al. (2017) Cardiac Myosin Binding Protein-C Autoantibodies are Potential Early Indicators of Cardiac Dysfunction and Patient Outcome in Acute Coronary Syndrome. JACC Basic Transl Sci 2:122-131
Lynch 4th, Thomas L; Ismahil, Mohamed Ameen; Jegga, Anil G et al. (2017) Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J Mol Cell Cardiol 102:83-93
Viswanathan, Shiv Kumar; Sanders, Heather K; McNamara, James W et al. (2017) Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PLoS One 12:e0187948
Sadayappan, Sakthivel (2017) The Myofilament Field Revisited in the Age of Cellular and Molecular Biology. Circ Res 121:601-603
Sadayappan, Sakthivel (2017) Cardiovascular Early Careers: Past and Present. Circ Res 121:100-102

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