BACKGROUND There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. OBJECTIVES We sought to elucidate the tissue level mechanisms underlying the therapeutic benefits of myocardial matrix injection. METHODS Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks post-injection. Whole transcriptome microarrays were performed on ribonucleic acid (RNA) isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histological quantification confirmed expression of key genes and their activation in altered pathways. RESULTS Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected controls. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing post-MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. CONCLUSIONS These results indicate that the myocardial matrix alters several key pathways post-MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.

TOC Entry Post-surgical cardiac adhesions increase surgery times as well as patient mortality and morbidity. We present a fast gelling oxime-crosslinked PEG hydrogel with tunable gelation time, degradation, and mechanical properties. This material is cytocompatible and prevents cellular adhesion. We demonstrate material retention on different cardiac tissues ex vivo over time and that functional group ratio alters material retention on different cardiac tissues.

We previously showed that the NO/cGMP/protein kinase G (PKG) signaling pathway positively regulates osteoblast proliferation, differentiation, and survival in vitro, and that cGMP‐elevating agents have bone‐anabolic effects in mice. Here, we generated mice with an osteoblast‐specific (OB) knockout (KO) of type 2 PKG (gene name Prkg2) using a Col1a1(2.3 kb)‐Cre driver. Compared to wild type (WT) littermates, 8‐week‐old male OB Prkg2‐KO mice had fewer osteoblasts, reduced bone formation rates, and lower trabecular and cortical bone volumes. Female OB Prkg2‐KO littermates showed no bone abnormalities, despite the same degree of PKG2 deficiency in bone. Expression of osteoblast differentiation‐ and Wnt/β‐catenin‐related genes was lower in primary osteoblasts and bones of male KO but not female KO mice compared to WT littermates. Osteoclast parameters were unaffected in both sexes. Since PKG2 is part of a mechano‐sensitive complex in osteoblast membranes, we examined its role during mechanical loading. Cyclical compression of the tibia increased cortical thickness and induced mechanosensitive and Wnt/β‐catenin‐related genes to a similar extent in male and female WT mice and female OB Prkg2‐KO mice, but loading had a minimal effect in male KO mice. We conclude that PKG2 drives bone acquisition and adaptation to mechanical loading via the Wnt/β‐catenin pathway in male mice. The striking sexual dimorphism of OB Prkg2‐KO mice suggests that current U.S. Food and Drug Administration‐approved cGMP‐elevating agents may represent novel effective treatment options for male osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).