Significant Reduction Of Hypertrophy Research Articles

Overlapping and differential functions of ATF6\u03b1 versus ATF6\u03b2 in the mouse heart

Hemodynamic stress on the mammalian heart results in compensatory hypertrophy and activation of the unfolded protein response through activating transcription factor 6α (ATF6α) in cardiac myocytes, but the roles of ATF6α or the related transcription factor ATF6β in regulating this hypertrophic response are not well-understood. Here we examined the effects of loss of ATF6α or ATF6β on the cardiac response to pressure overload. Mice gene-deleted for Atf6 or Atf6b were subjected to 2 weeks of transverse aortic constriction, and each showed a significant reduction in hypertrophy with reduced expression of endoplasmic reticulum (ER) stress-associated proteins compared with controls. However, with long-term pressure overload both Atf6 and Atf6b null mice showed enhanced decompensation typified by increased heart weight, pulmonary edema and reduced function compared to control mice. Our subsequent studies using cardiac-specific transgenic mice expressing the transcriptionally active N-terminus of ATF6α or ATF6β revealed that these factors control overlapping gene expression networks that include numerous ER protein chaperones and ER associated degradation components. This work reveals previously unappreciated roles for ATF6α and ATF6β in regulating the pressure overload induced cardiac hypertrophic response and in controlling the expression of genes that condition the ER during hemodynamic stress.

2018 AHA Late-Breaking Basic Science Abstracts.

2018 AHA Late-Breaking Basic Science Abstracts.

Sarcomere-based genetic enhancement of systolic cardiac function in a murine model of dilated cardiomyopathy

Diminished cardiac contractile function is a characteristic feature of dilated cardiomyopathy (DCM) and many other heart failure (HF) causing etiologies. We tested the hypothesis that targeting the sarcomere to increase cardiac contractility can effectively prevent the DCM phenotype in muscle-LIM protein knockout (MLP−/−) mice. The ablation of cardiac myosin binding protein C (MYBPC3−/−) protected the MLP−/− mice from developing the DCM phenotype. We examined the in vivo cardiac function and morphology of the resultant mouse model lacking both MLP and MYBPC3 (DKO) by echocardiography and pressure-volume catheterization and found a significant reduction in hypertrophy, as evidenced by normalized wall thickness and chamber dimensions, and improved systolic function, as evidenced by enhanced ejection fraction (~26% increase compared MLP−/− mice) and rate of pressure development (DKO 7851.0 ± 504.8 vs. MLP−/− 4496.4 ± 196.8 mmHg/s). To investigate the molecular basis for the improved DKO phenotype we performed mechanical experiments in skinned myocardium isolated from WT and the individual KO mice. Skinned myocardium isolated from DKO mice displayed increased Ca2+ sensitivity of force generation, and significantly accelerated rate of cross-bridge detachment (+63% compared to MLP−/−) and rate of XB recruitment (+58% compared to MLP−/−) at submaximal Ca2+ activations. The in vivo and in vitro functional enhancement of DKO mice demonstrates that enhancing the sarcomeric contractility can be cardioprotective in HF characterized by reduced cardiac output, such as in cases of DCM.

Abstract 360: Differential Analysis of Thrombospondin Proteins in Cardiac Disease

Thrombospondin (Thbs) proteins are multidomain, matricellular proteins comprised of 5 genes that each share similar domains and have been largely ascribed the same functional characteristics The Thbs protein family is divided in 2 subgroups based on multimerization as trimers, (group A: Thbs1 and 2), or as pentamers (group B: Thbs3, 4 and 5). Thbs proteins modulate aspects of cell- matrix interactions, and more recently we have shown that they can also serve an intracellular chaperone function along the secretory pathway in response to ER stress. Thbs1 and 2 can also alter angiogenesis and modulate MMP activity as well as TGFb activity. The overall aim of this study is to functionally compare the two Thbs subgroups and elucidate their involvement in cardiac homeostasis and disease. Hence we analyzed Thbs1 as a representative of group A and Thbs3 for group B. Cardiomyocyte specific overexpression of either Thbs1 or Thbs3 results in robust activation of an ATF6- dependent ER stress response, similar to our previous working published with Thbs4. However, Thbs1 overexpressing mice suffer from cardiomyopathy and die within 12 weeks. In contrast, Thbs3 overexpressing mice are completely normal at baseline and Thbs3 overexpression even increased survival rates after MI similar to Thbs4 from our previous work. However, Thbs3 hearts also showed increased chamber dilation after MI and lower heart function suggesting that Thbs3 also has maladaptive effects. In contrast to loss of Thbs4, which die within the first week of TAC mediated pressure overload, Thbs3 KO mice are protected from TAC induced hypertrophy. Moreover, the combination of Thbs3/4 dKO more closely phenocopies the effect of Thbs3 deletion, as these mice show a significant reduction in hypertrophy and lung congestion after long term TAC. This is the first study comparing the function of different Thbs isoforms in the heart, which suggests a novel role of Thbs3.

A PROTEIN WITH ANTI-FIBROTIC POTENTIAL FOUND IN THE PROTEOME OF PATIENTS WITH HYPERTENSIVE HEART DISEASE

PurposeHeart failure with preserved ejection fraction (HFPEF) contributes to 20–50% of the heart failure population. Excessive fibrosis in the cardiac interstitium results in stiffness and reduced compliance of the left...

The influence of oestrogen‐deficiency and ACE inhibition on the progression of myocardial hypertrophy in spontaneously hypertensive rats

ACE inhibitors are widely used to antagonize the biological activity of angiotensin II in hypertensive heart disease. Oestrogen reduces angiotensin type 1 receptor expression, and thereby modifies angiotensin signalling. To investigate the interaction of oestrogen status and ACE inhibition on the development of left ventricular hypertrophy and expression of transforming growth factor (TGF)-beta(1) in female spontaneously hypertensive rats (SHR). Intact female SHR, ovariectomised SHR, and ovariectomised SHR with 17beta-oestradiol (E2) replacement therapy were either treated with placebo or the ACE inhibitor moexiprilat. Blood pressure, left ventricular hypertrophy, and expression of TGF-beta(1) and TGF-beta(1)-regulated genes were investigated. ACE inhibition reduced blood pressure in all groups. When normalised to blood pressure, a significant reduction in hypertrophy was found in ovariectomised animals receiving E2. Expression of TGF-beta(1) was increased in all three groups treated with the ACE inhibitor, with top levels in ovariectomised animals. Moreover, expression of ornithine decarboxylase (ODC), an adrenoceptor dependent gene, downstream of TGF-beta(1), was up-regulated upon ACE inhibition, except in animals which were ovariectomised and oestrogen supplemented. Parathyroid hormone-related peptide, a growth factor negatively regulated by TGF-beta(1), was down-regulated in all animals receiving the ACE inhibitor. ACE inhibition modulated TGF-beta(1) and TGF-beta(1) dependent genes. Oestrogen deficiency alone did not influence the progression of cardiac hypertrophy in this model of female SHR.