Mechanotransduction in Cardiac Hypertrophy and Failure

Lyon, Robert C.; Zanella, Fabian; Omens, Jeffrey H.; Sheikh, Farah

doi:10.1161/circresaha.116.304937

Cited by 265 publications

(210 citation statements)

References 170 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…2012, 2013) and induced the regression of coronary vessels and caused the dearth of hibernating myocytes in the infarct zone, the mechanisms of which should be investigated in relation to the mechanobiology of myocytes (Lyon et al. 2015). Moreover, a comparison of multiple coronary artery ligations with the traditional LCX ligation should be performed in future studies.…”

Section: Discussionmentioning

confidence: 99%

The Structure-function remodeling in rabbit hearts of myocardial infarction

Niu

et al. 2017

Physiol Rep

View full text Add to dashboard Cite

Animal models are of importance to investigate basic mechanisms for ischemic heart failure (HF). The objective of the study was to create a rabbit model through multiple coronary artery ligations to investigate the postoperative structure‐function remodeling of the left ventricle (LV) and coronary arterial trees. Here, we hypothesize that the interplay of the degenerated coronary vasculature and increased ventricle wall stress relevant to cardiac fibrosis in vicinity of myocardial infarction (MI) precipitates the incidence and progression of ischemic HF. Echocardiographic measurements showed an approximately monotonic drop of fractional shortening and ejection fraction from 40% and 73% down to 28% and 58% as well as persistent enlargement of LV cavity and slight mitral regurgitation at postoperative 12 weeks. Micro‐CT and histological measurements showed that coronary vascular rarefaction and cardiac fibrosis relevant to inflammation occurred concurrently in vicinity of MI at postoperative 12 weeks albeit there was compensatory vascular growth at postoperative 6 weeks. These findings validate the proposed rabbit model and prove the hypothesis. The post‐MI rabbit model can serve as a reference to test various drugs for treatment of ischemic HF.

show abstract

Section: Discussionmentioning

confidence: 99%

The Structure-function remodeling in rabbit hearts of myocardial infarction

Niu

et al. 2017

Physiol Rep

View full text Add to dashboard Cite

show abstract

“…Maintenance of cardiac integrity also depends on the link between adjacent CMs mediated by the intercalated disks (ICD) (30,31). Although Tln is mainly localized at costameres, it has also been detected at low levels in ICDs (17).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

show abstract

“…Remodeling and adaptation are crucial properties of the myocardium and allow the heart to respond to changes in workload. Many molecules have been identified as cardiac mechanosensors and integrators of stress, all essential to preserve cardiac function (2). However, our understanding of the fundamental processes and early events that allow the myocardium to sense environmental cues and adapt accordingly is still limited.…”

mentioning

confidence: 99%