AG Kraft
Hypertrophic Cardiomyopathy: Contractile Imbalance as a central pathomechanism? Investigations on human myocardium and cellular models.
Research focus
One of our primary goals is to elucidate how mutations in sarcomeric proteins disrupt sarcomere function in cardiomyocytes and can lead to the clinical picture of hypertrophic cardiomyopathy (HCM).
A key finding is our observation that functional changes in the myocardium of affected heterozygous patients caused by HCM mutations vary greatly from cell to cell. For example, some cardiomyocytes exhibit significantly reduced force generation at physiological calcium concentrations, while others behave like healthy cardiomyocytes at the same calcium levels, as if no mutated protein were expressed in these cells. We have now been able to demonstrate for the genes encoding β-cardiac myosin (β-MyHC), cardiac troponin I (cTnI), and cardiac myosin-binding protein C (cMyBP-C) that highly variable proportions of mutated and wild-type mRNA are expressed in the individual cardiomyocytes of HCM patients. This most likely leads to correspondingly different proportions of mutated and wild-type protein and thus to the observed variability in biomechanical function. Our hypothesis is that the resulting functional variability between neighboring cardiomyocytes in the myocardial cellular network causes distortions in the cells, leading to typical features of HCM such as myofibrillar and cellular disarray, hypertrophy, and fibrosis (the “contractile imbalance” hypothesis)
We have now been able to show that the cell-to-cell variability in the proportion of mutated mRNA is most likely due to the fact that the mutated and wild-type alleles are transcribed independently of one another in random bursts. Model calculations confirmed the hypothesis that independent, burst-like transcription of the two respective alleles can lead to different proportions of mutated and wild-type protein in individual cardiomyocytes and thus to the observed functional variability. According to this concept, a mutation in a sarcomeric or non-sarcomeric protein (e.g., kinases) that results in a change in the biomechanical function of the sarcomere or myofibrils can lead, via random, burst-like transcription, to functional imbalance among individual cardiomyocytes and thus contribute to the development of HCM.
Aims are to identify primary functional effects of HCM mutations also in other sarcomeric proteins at the molecular level and to characterize them from cell to cell by investigating myocardial tissue from HCM patients. Furthermore, we analyze changes in signaling pathways at the single cell level, which are induced due to contractile imbalance and which can lead to hypertrophy and fibrosis. Finally, it is of great importance to elucidate mechanisms of burst-like transcription of the affected genes for sarcomeric proteins in cardiomyocytes to be able to modulate the expression, aiming at new therapeutic approaches.
Our goal is to identify the primary functional effects of HCM mutations in other sarcomeric proteins at the molecular level through analyses of myocardial tissue from HCM patients and to characterize these effects on a cell-by-cell basis. Furthermore, we analyze changes in signaling pathways at the single-cell level that are induced by contractile imbalance and can lead to hypertrophy and fibrosis. Finally, it is of great importance to elucidate the mechanisms of burst-like transcription of the affected genes encoding sarcomeric proteins in cardiomyocytes in order to modulate their expression and identify new therapeutic targets.
These points are being investigated in collaboration with the research groups led by Konze, Kowalski, Iorga, Montag (MSB, Berlin), and Weber (IMTTS, MHH) using myocardial tissue from HCM patients as well as cellular models based on stem cell-derived cardiomyocytes carrying HCM mutations. Cell culture models allow us not only to further investigate the contractile imbalance hypothesis but also to derive new pharmacological intervention strategies for the early prevention of HCM development. Last but not least, by investigating the primary functional effects of HCM mutations, we also gain insights into the relevance of individual proteins and their subdomains for sarcomere function.
Group members
Prof. Dr. rer. nat. Theresia Kraft
Dipl. Ing. (FH) Faramarz Matinmehr
Dr. rer. nat. Joachim Meissner
Qualification work
cand med. Vanessa Dieling
Publicationen
General list of publications of the institute
Funding
- Transkription sarkomerischer Gene in Bursts als Pathogenesefaktor der Hypertrophen Kardiomyopathie.
Laufzeit: 12/2022 - 10/2026, Mittelgeber: Deutsche Forschungsgemeinschaft
- Kontraktiles Ungleichgewicht zwischen Kardiomyozyten als pathoge-netischer Faktor der Hypertrophen Kardiomyopathie – Untersuchungen an Kardiomyozyten aus humanen pluripotenten Stammzellen mit cMyBP-C-Mutationen. Laufzeit: 05/2021 - 04/2027, Mittelgeber: Deutsche Forschungsgemeinschaft
Teaching
- Lecture in "Physiology and Physical Basics of Medicine" for students of human medicine (HM) and "Physik-Physiologie" dentistry (ZM) in the 1st and 2nd year of study on the topics of skeletal muscle, smooth muscle, vegetative nervous system, heart, blood, acid-base balance, energy expenditure, exercise physiology
- Lecture in “Clinical Medicine 1” for medicine students (3rd year of study) on the subjects of thrombosis/embolism, pneumonia, heart failure
- Lecture in "Physiology" in the interdisciplinary bachelor course in biology of the Leibniz University, Hannover Veterinary School and Hannover Medical School on the subjects of skeletal muscle, smooth muscle, heart
- Lecture in "Physiology" in the master course in biomedicine of Hannover Medical School on the subjects vegetative nervous system, heart
- Practical training in "Physiology and Physical Basics of Medicine" for students of medicine and biology and " Physik-Physiologie" dentistry on various topics
- Seminars in "Physiology and Physical Basics of Medicine" for medicine students on various subjects
Teaching of the Center Physiology