Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity

Kaakinen, Mika, Reichelt, Melissa E., Ma, Zhibin, Ferguson, Charles, Martel, Nick, Porrello, Enzo R., Hudson, James E., Thomas, Walter G., Parton, Robert G. and Headrick, John P. (2017) Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity. Basic Research in Cardiology, 112 3: . doi:10.1007/s00395-017-0613-6


Author Kaakinen, Mika
Reichelt, Melissa E.
Ma, Zhibin
Ferguson, Charles
Martel, Nick
Porrello, Enzo R.
Hudson, James E.
Thomas, Walter G.
Parton, Robert G.
Headrick, John P.
Title Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity
Journal name Basic Research in Cardiology   Check publisher's open access policy
ISSN 1435-1803
0300-8428
Publication date 2017-05-01
Sub-type Article (original research)
DOI 10.1007/s00395-017-0613-6
Open Access Status Not yet assessed
Volume 112
Issue 3
Total pages 19
Place of publication Heidelberg, Germany
Publisher Springer Medizin
Collection year 2018
Language eng
Formatted abstract
Caveolae and associated cavin and caveolins may govern myocardial function, together with responses to mechanical and ischaemic stresses. Abnormalities in these proteins are also implicated in different cardiovascular disorders. However, specific roles of the cavin-1 protein in cardiac and coronary responses to mechanical/metabolic perturbation remain unclear. We characterised cardiovascular impacts of cavin-1 deficiency, comparing myocardial and coronary phenotypes and responses to stretch and ischaemia–reperfusion in hearts from cavin-1+/+ and cavin-1−/− mice. Caveolae and caveolins 1 and 3 were depleted in cavin-1−/− hearts. Cardiac ejection properties in situ were modestly reduced in cavin-1−/− mice. While peak contractile performance in ex vivo myocardium from cavin-1−/− and cavin-1+/+ mice was comparable, intrinsic beating rate, diastolic stiffness and Frank–Starling behaviour (stretch-dependent diastolic and systolic forces) were exaggerated in cavin-1−/− hearts. Increases in stretch-dependent forces were countered by NOS inhibition (100 µM L-NAME), which exposed negative inotropy in cavin-1−/− hearts, and were mimicked by 100 µM nitroprusside. In contrast, chronotropic differences appeared largely NOS-independent. Cavin-1 deletion also induced NOS-dependent coronary dilatation, ≥3-fold prolongation of reactive hyperaemic responses, and exaggerated pressure-dependence of coronary flow. Stretch-dependent efflux of lactate dehydrogenase and cardiac troponin I was increased and induction of brain natriuretic peptide and c-Fos inhibited in cavin-1−/− hearts, while ERK1/2 phospho-activation was preserved. Post-ischaemic dysfunction and damage was also exaggerated in cavin-1−/− hearts. Diverse effects of cavin-1 deletion reveal important roles in both NOS-dependent and -independent control of cardiac and coronary functions, together with governing sarcolemmal fragility and myocardial responses to stretch and ischaemia.
Keyword Cardiac compliance
Caveolar proteins
Ischaemia–reperfusion
Membrane permeability
Nitric oxide synthase
Reactive hyperaemia
Stretch-response
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
 
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