Daily Cardiology Research Analysis

Cardiac allograft vasculopathy (CAV) is the leading cause of mortality after heart transplantation, yet no targeted therapies exist to prevent or reverse disease progression, and patients with CAV ultimately require a retransplant. CAV is characterized by progressive neointimal hyperplasia in donor coronary arteries, resulting in luminal occlusion and eventual allograft failure. Although immune and stromal cell interactions are thought to drive disease, the key cellular and molecular mechanisms remain poorly defined. Here we integrate single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to characterize the CAV neointimal microenvironment. By comparing arteries with CAV with atherosclerotic coronary artery disease and non-diseased controls, we identify a distinct transcriptional signature of CAV. Our analysis reveals that modulated vascular smooth muscle cells and macrophage subsets dominate the neointima and interact to promote type 1 interferon (IFN)-mediated inflammation. Using a mouse model of CAV, we show that IFN signaling blockade with ruxolitinib significantly reduces CAV incidence and prolongs allograft survival. These findings define key cellular drivers of CAV and highlight IFN signaling as a potential therapeutic target.

BACKGROUND AND AIMS: Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction. METHODS: RNA sequencing was performed in naturally aged mice with and without voluntary exercise. Functional studies of candidate lncRNAs were conducted using AAV-mediated overexpression, antisense oligonucleotides, and CRISPR-based knockdown, both in vivo and in endothelial cells (ECs). RESULTS: A novel set of lncRNAs altered in hearts from exercised aged mice was identified and termed Senescence Associated LncRNA Transcripts in Exercise (SALTes). Among these, SALTe1 is evolutionarily conserved and enriched in ECs. SALTe1 expression is elevated in hearts from aged mice and in patients with various types of heart failure but suppressed by exercise. In 20-month-old mice, SALTe1 inhibition, via antisense GapmeRs or EC-specific deletion, attenuated endothelial senescence, restored microvascular perfusion, and improved diastolic function. Mechanistic studies showed that SALTe1 acts, at least in part, through upregulation of PARP9. CONCLUSIONS: These findings establish SALTe1 as a pivotal regulator of endothelial senescence as well as microvascular and cardiac dysfunction in ageing. Targeted inhibition of SALTe1 recapitulates the vasculoprotective effects of exercise, highlighting a tractable antisense-based therapeutic strategy for combating age-related cardiac decline.

BACKGROUND: Heart failure remains a major global health burden, driven largely by pathological cardiac hypertrophy. Mitochondrial dysfunction, particularly impaired mitochondrial complex I activity, is central to the disease progression, yet its regulatory mechanisms are poorly understood. Cross-species transcriptomic screening and UK Biobank analyses identified SBK2 (Src homology 3 domain-binding kinase 2) as a conserved, cardiac-enriched kinase potentially linked to heart failure risk. We hypothesized that SBK2 regulates cardiac hypertrophy by modulating mitochondrial complex I function. METHODS: Cross-species conserved genes were identified from GEO data sets, and variants within ±10 kb of SBK2, ADAMTSL2 (ADAMTS-like protein 2), LOX, and SPP1 (secreted phosphoprotein 1) were assessed for heart failure association in the UK Biobank cohort. SBK2 expression was examined in experimental models and publicly available human hypertrophic cardiomyopathy data sets, and its function was investigated through loss- and gain-of-function studies in cardiomyocytes and mice. The substrates and interacting partners of SBK2 were identified by proteomic and interactome analyses and validated by in vitro kinase assays and coimmunoprecipitation. Mitochondrial protein import and respiratory supercomplex assembly were assessed by biochemical fractionation and blue native PAGE. RESULTS: SBK2 expression was reduced in hypertrophic hearts and primary neonatal rat ventricular myocytes. Cardiomyocyte-specific overexpression of SBK2 attenuated hypertrophy and fibrosis, improved systolic function, and suppressed maladaptive gene expression. Conversely, SBK2 knockdown exacerbated these phenotypes. Mechanistically, SBK2 directly bound and phosphorylated NDUFV1 (NADH: ubiquinone oxidoreductase core subunit V1) at serine 251. This modification enhanced the interaction between NDUFV1 and the cytosolic chaperone HSPA1A and facilitated TOM70-dependent mitochondrial import. Increased mitochondrial NDUFV1 promoted complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis. Pharmacological inhibition of complex I or NDUFV1 silencing abolished SBK2-mediated protection. Moreover, a phospho-deficient NDUFV1 mutant (S251A) failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes. CONCLUSIONS: SBK2 is an upstream kinase that couples cytosolic signaling to mitochondrial protein import by phosphorylating NDUFV1, thereby sustaining complex I integrity and mitochondrial function to restrain pathological cardiac hypertrophy. These findings uncover a previously unrecognized SBK2-NDUFV1 signaling axis linking kinase signaling to mitochondrial proteostasis and identify a potential therapeutic target for heart failure.