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Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

ABSTRACT: Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.

SUBMITTER: Shettigar V

PROVIDER: S-EPMC4770086 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

Shettigar Vikram V Zhang Bo B Little Sean C SC Salhi Hussam E HE Hansen Brian J BJ Li Ning N Zhang Jianchao J Roof Steve R SR Ho Hsiang-Ting HT Brunello Lucia L Lerch Jessica K JK Weisleder Noah N Fedorov Vadim V VV Accornero Federica F Rafael-Fortney Jill A JA Gyorke Sandor S Janssen Paul M L PM Biesiadecki Brandon J BJ Ziolo Mark T MT Davis Jonathan P JP

Nature communications 20160224

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failu ...[more]

PMID: 26908229

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Project description:BackgroundHigh-sensitivity cardiac troponin T (hs-cTnT) in serum is a useful marker of acute myocardial injury, yet information is limited in patients with chronic obstructive pulmonary disease. We aimed to explore the association between hs-cTnT levels and cardiac and pulmonary dysfunction in patients with stable chronic obstructive pulmonary disease and at-risk individuals.MethodsWe examined community-dwelling adults with/without chronic obstructive pulmonary disease, with a life-long smoking history, current symptoms of dyspnea during exertion, prolonged coughing, and/or sputum. Serum hs-cTnT concentrations were measured, and subjects underwent pulmonary function tests, high-resolution computed tomography of the chest, an echocardiogram, and a 6-minute walking test.ResultsEighty-six stable patients were identified (mean age 65.5 years; predicted forced expiratory volume in 1 second [FEV1% predicted] 75.0%). Their overall mean hs-cTnT level was 0.008 ng/mL. Logarithmically transformed hs-cTnT levels significantly and positively correlated with age, smoking index, serum high-sensitivity C-reactive protein levels, right ventricle systolic pressure, low attenuation area percentage, and brain natriuretic peptide levels (range r=0.231-0.534, P=0.000 to P=0.042). Further, logarithmically transformed hs-cTnT values significantly and negatively correlated with forced vital capacity, FEV1% predicted, diffusion capacity, arterial oxygen tension, and 6-minute walking distance (range r= -0.482 to -0.377, P=0.000 to P=0.002). Multivariate analyses showed that hs-cTnT values varied independently according to the following three parameters: high-sensitivity C-reactive protein levels (B=0.157, β=0.450, t=3.571, P=0.001), age (B=0.008, β=0.352, t=2.789, P=0.009), and right ventricular systolic pressure (B=0.008, β=0.280, t=2.202, P=0.035).ConclusionEven in patients with stable chronic obstructive pulmonary disease, the serum troponin T concentration was controlled by at least three major factors, ie, systemic inflammation, advancing age, and right cardiac overload.

Dataset Information

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

Publications

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

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