Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine‐protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation– induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte‐specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain‐ and loss‐of‐function experiments using cardiomyocyte‐specific adeno‐associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK‐3β (glycogen synthase kinase‐3β) activity and upregulating β‐catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S‐specific cyclin‐D1, c‐myc (cellular‐myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

Abnormalities in programmed cell death (PCD) signaling cascades can be observed in the development and progression of various cardiovascular diseases, such as apoptosis, necrosis, pyroptosis, ferroptosis, and cell death associated with autophagy. Aberrant activation of PCD pathways is a common feature leading to excessive cardiac remodeling and heart failure, involved in the pathogenesis of various cardiovascular diseases. Conversely, timely activation of PCD remodels cardiac structure and function after injury in a spatially or temporally restricted manner and corrects cardiac development similarly. As many cardiovascular diseases exhibit abnormalities in PCD pathways, drugs that can inhibit or modulate PCD may be critical in future therapeutic strategies. In this review, we briefly describe the process of various types of PCD and their roles in the occurrence and development of cardiovascular diseases. We also discuss the interplay between different cell death signaling cascades and summarize pharmaceutical agents targeting key players in cell death signaling pathways that have progressed to clinical trials. Ultimately a better understanding of PCD involved in cardiovascular diseases may lead to new avenues for therapy.

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Cardiovascular disease (CVD) remains the leading cause of death worldwide. Therefore, exploring the mechanism of CVDs and critical regulatory factors is of great significance for promoting heart repair, reversing cardiac remodeling, and reducing adverse cardiovascular events. Recently, significant progress has been made in understanding the function of protein kinases and their interactions with other regulatory proteins in myocardial biology. Protein kinases are positioned as critical regulators at the intersection of multiple signals and coordinate nearly every aspect of myocardial responses, regulating contractility, metabolism, transcription, and cellular death. Equally, reconstructing the disrupted protein kinases regulatory network will help reverse pathological progress and stimulate cardiac repair. This review summarizes recent researches concerning the function of protein kinases in CVDs, discusses their promising clinical applications, and explores potential targets for future treatments.

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The mammalian heart possesses entire regeneration capacity after birth, which is lost in adulthood. The role of the kinase network in myocardial regeneration remains largely elusive. SGK3 (threonine-protein kinase 3) is a functional kinase we identified previously with the capacity to promote cardiomyocyte proliferation and cardiac repair after myocardial infarction. However, the upstream signals regulating SGK3 are still unknown. Based on the quantitative phosphoproteomics data and pulldown assay, we identified cyclin-dependent kinase 9 (CDK9) as a novel therapeutic target in regeneration therapy. The direct combination between CDK9 and SGK3 was further confirmed by co-immunoprecipitation (Co-IP). CDK9 is highly expressed in the newborn period and rarely detected in the adult myocardium. In vitro, the proliferation ratio of primary cardiomyocytes was significantly elevated by CDK9 overexpression while inhibited by CDK9 knockdown. In vivo, inhibition of CDK9 shortened the time window of cardiac regeneration after apical resection (AR) in neonatal mice, while overexpression of CDK9 significantly promoted mature cardiomyocytes (CMs) to re-enter the cell cycle and cardiac repair after myocardial infarction (MI) in adult mice. Mechanistically, CDK9 promoted cardiac repair by directly activating SGK3 and downstream GSK-3β/β-catenin pathway. Consequently, our study indicated that CDK9 might be a novel target for MI therapy by stimulating myocardial regeneration.

Myocardial fibrosis, a common pathological manifestation of cardiac remodeling (CR), often leads to heart failure (HF) and even death. The underlying molecular mechanism of the role of TRIM33 in Ang II–induced myocardial fibrosis is not fully understood. We found that TRIM33 was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. Adult mice induced by Ang II were used as in vivo models, and Ang II–induced neonatal mouse primary cardiac fibroblasts (CFs) were used as in vitro models. The level of CF fibrosis in vitro was assessed by CF proliferation, migration, activation and extracellular matrix (ECM) synthesis. In addition, Masson staining, the heart weight/body weight (HW/BW) ratio and echocardiography were used to evaluate the in vivo effect of TRIM33. TRIM33 expression was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. In in vitro experiments, we found that TRIM33 knockdown promoted Ang II–induced CF proliferation, while TRIM33 overexpression weakened Ang II–induced CF proliferation, migration, activation and collagen synthesis. Mechanistically, we showed that TRIM33, negatively regulated by HSPB5, mediated its antifibrotic effect by inhibiting the activation of TGF-β1 and its downstream genes, Smad3 and Smad4. Finally, TRIM33 overexpression suppressed fibrosis and promoted cardiac repair and functional recovery in Ang II–induced mice. Our results clearly establish that TRIM33 limits cardiac fibrosis by hindering CF proliferation, migration, activation and collagen synthesis. Enhancing these beneficial functions of TRIM33 by a targeting vector might be a novel therapeutic strategy for CR.

To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.