Volume 3 Issue 7, July 2024

In response to high fluid shear stress, KLF2-mediated induction of the BMP inhibitor BMPER improves outward arterial remodeling. This knowledge is translated into a preclinical model showing that BMP9 and BMP10 neutralizing antibodies enhance flow recovery and arterialization in ischemia in diabetic mice.

Myocardial infarction can damage the heart muscle and lead to heart failure. Research on recovery typically focuses on infiltrating immune cells, damaged cardiomyocytes, over-stimulated fibroblasts and changes in vasculature. Haykin et al. now describe a multi-organ circuit linking these entities, including the brain and liver, in the repair process.

Myofibroblast activation requires nuclear translocation of ATP citrate lyase (ACLY) that triggers chromatin remodeling and the induction of fibrosis-associated genes. ACLY inhibition prevents myofibroblast conversion and causes de-differentiation of myofibroblasts to fibroblasts, indicating a potential therapeutic approach for heart failure.

Deng et al. show that endothelial cells respond to high fluid shear stress by KLF2-mediated induction of the BMP–Smad1/5 pathway inhibitor BMPER, resulting in outward vessel remodeling, and apply this knowledge to develop an approach that improves vessel remodeling in mouse models of diabetes.

Prabhakar et al. demonstrate in rats with mitomycin C-caused pulmonary veno-occlusive disease activation of protein kinase R (PKR) and the integrated stress response (ISR), leading to the depletion of VE-cadherin and RAD51 from endothelial junctions, endothelial barrier disruption and vascular remodeling. Inhibiting the PKR–ISR axis protects against mitomycin C-induced endothelial damage.

Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.

Haykin et al. show that activation of the brain’s reward system modulates adrenergic input to the liver and complement component 3 transcription, affecting vascularization and improving cardiac recovery after acute myocardial infarction.

Sakata et al. performed a prospective personalized mechanistic computational (digital twin) study focused on characterizing the arrhythmogenic properties of the atrial fibrotic substrate in patients with persistent atrial fibrillation, and they introduce here a novel mechanism-oriented strategy for optimal ablation.

Elrod and colleagues reveal the role of ATP-citrate lyase in myofibroblast differentiation and cardiac fibrosis.