alpha-B Crystallin Reverses High Diastolic Stiffness of Failing Human Cardiomyocytes

作者：Franssen Constantijn; Kole Jeroen; Musters Rene; Hamdani Nazha; Paulus Walter J^*

来源：Circulation-Heart Failure, 2017, 10(3): e003626.

DOI：10.1161/CIRCHEARTFAILURE.116.003626

• aortic valve stenosis
• collagen
• diastole
• extracellular matrix
• heat shock proteins

Background-Cardiomyocytes with a less distensible titin and interstitial collagen contribute to the high diastolic stiffness of failing myocardium. Their relative contributions and mechanisms underlying loss of titin distensibility were assessed in failing human hearts.
Methods and Results-Left ventricular tissue was procured in patients with aortic stenosis (AS, n= 9) and dilated cardiomyopathy (DCM, n= 6). Explanted donor hearts (n= 8) served as controls. Stretches were performed in myocardial strips, and an extraction protocol differentiated between passive tension (F-passive) attributable to cardiomyocytes or to collagen. F-passive -cardiomyocytes was higher in AS and DCM at shorter muscle lengths, whereas F passive -collagen was higher in AS at longer muscle lengths and in DCM at shorter and longer muscle lengths. Cardiomyocytes were stretched to investigate titin distensibility. Cardiomyocytes were incubated with alkaline phosphatase, subsequently reassessed after a period of prestretch and finally treated with the heat shock protein alpha-B crystallin. Alkaline phosphatase shifted the F-passive -sarcomere length relation upward only in donor. Prestretch shifted the F passive -sarcomere length relation further upward in donor and upward in AS and DCM. a-B crystallin shifted the F-passive -sarcomere length relation downward to baseline in donor and to lower than baseline in AS and DCM. In failing myocardium, confocal laser microscopy revealed alpha-B crystallin in subsarcolemmal aggresomes.
Conclusions-High cardiomyocyte stiffness contributed to stiffness of failing human myocardium because of reduced titin distensibility. The latter resulted from an absent stiffness-lowering effect of baseline phosphorylation and from titin aggregation. High cardiomyocyte stiffness was corrected by a-B crystallin probably through relief of titin aggregation.

• 出版日期2017-3