ABSTRACT
This article comments on: Li Z, Zhang D, Liang X, Liang J. 2024. Receptor for Activated C Kinase 1 counteracts ABSCISIC ACID INSENSITIVE5-mediated inhibition of seed germination and post-germinative growth in Arabidopsis. Journal of Experimental Botany 75, 3932-3945.
Subject(s)
Abscisic Acid , Arabidopsis Proteins , Arabidopsis , Signal Transduction , Abscisic Acid/metabolism , Arabidopsis/metabolism , Arabidopsis/growth & development , Arabidopsis/genetics , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Germination , Plant Growth Regulators/metabolismABSTRACT
Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-ß galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.
ABSTRACT
BACKGROUND: Transthyretin cardiac amyloidosis (ATTR amyloidosis) is a frequent etiology of heart failure. Inflammation and mineral metabolism are associated with myocardial dysfunction and clinical performance. Cardiac global longitudinal strain (GLS) allows function assessment and is associated with prognosis. Our aim was to describe possible correlations between GLS, biomarker levels and clinical performance in ATTR amyloidosis. METHODS: Thirteen patients with ATTR amyloidosis were included. Clinical characteristics; echocardiographic features, including strain assessment and 6 min walk test (6MWT); and baseline inflammatory, mineral metabolism and cardiovascular biomarker levels were assessed. RESULTS: Of the 13 patients, 46.2% were women, and the mean age was 79 years. TAPSE correlated with NT-ProBNP (r -0.65, p < 0.05) and galectin-3 (r 0.76, p < 0.05); E/E' ratio correlated with hsCRP (r 0.58, p < 0.05). Left ventricular GLS was associated with NT-ProBNP (r 0.61, p < 0.05) (patients have a better prognosis if the strain value is more negative) and left atrial GLS with NT-ProBNP (r -0.73, p < 0.05) and MCP1 (r 0.55, p < 0.05). Right ventricular GLS was correlated with hsTnI (r 0.62, p < 0.05) and IL6 (r 0.881, p < 0.05). Klotho levels were correlated with 6MWT (r 0.57, p < 0.05). CONCLUSIONS: While inflammatory biomarkers were correlated with cardiac function, klotho levels were associated with clinical performance in the population with TTR-CA.
ABSTRACT
Nitric oxide (NO) is a gasotransmitter required in a broad range of mechanisms controlling plant development and stress conditions. However, little is known about the specific role of this signaling molecule during lipid storage in the seeds. Here, we show that NO is accumulated in developing embryos and regulates the fatty acid profile through the stabilization of the basic/leucine zipper transcription factor bZIP67. NO and nitro-linolenic acid target and accumulate bZIP67 to induce the downstream expression of FAD3 desaturase, which is misregulated in a non-nitrosylable version of the protein. Moreover, the post-translational modification of bZIP67 is reversible by the trans-denitrosylation activity of peroxiredoxin IIE and defines a feedback mechanism for bZIP67 redox regulation. These findings provide a molecular framework to control the seed fatty acid profile caused by NO, and evidence of the in vivo functionality of nitro-fatty acids during plant developmental signaling.
Subject(s)
Arabidopsis Proteins , Basic-Leucine Zipper Transcription Factors , Fatty Acids , Peroxiredoxins , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Fatty Acids/metabolism , Gene Expression Regulation, Plant , Lipid Metabolism , Nitric Oxide/metabolism , Peroxiredoxins/metabolism , Protein Processing, Post-Translational , Seeds/metabolismABSTRACT
Introduction: The presence of non-coronary atherosclerosis (NCA) in patients with coronary artery disease is associated with a poor prognosis. We have studied whether NCA is also a predictor of poorer outcomes in patients undergoing coronary artery bypass grafting (CABG). Materials and methods: This is an observational study involving 567 consecutive patients who underwent CABG. Variables and prognosis were analysed based on the presence or absence of NCA, defined as previous stroke, transient ischaemic attack (TIA), or peripheral artery disease (PAD) [lower extremity artery disease (LEAD), carotid disease, previous lower limb vascular surgery, or abdominal aortic aneurysm (AAA)]. The primary outcome was a combination of TIA/stroke, acute myocardial infarction, new revascularization procedure, or death. The secondary outcome added the need for LEAD revascularization or AAA surgery. Results: One-hundred thirty-eight patients (24%) had NCA. Among them, traditional cardiovascular risk factors and older age were more frequently present. At multivariate analysis, NCA [hazard ratio (HR) = 1.84, 95% confidence interval (CI) 1.27-2.69], age (HR = 1.35, 95% CI 1.09-1.67, p = 0.004), and diabetes mellitus (HR = 1.50, 95% CI 1.05-2.15, p = 0.025), were positively associated with the development of the primary outcome, while estimated glomerular filtration rate (HR = 0.86, 95% CI 0.80-0.93, p = 0.001) and use of left internal mammary artery (HR = 0.36, 95% CI 0.15-0.82, p = 0.035), were inversely associated with this outcome. NCA was also an independent predictor of the secondary outcome. Mortality was also higher in NCA patients (27.5% vs. 9%, p < 0.001). Conclusions: Among patients undergoing CABG, the presence of NCA doubled the risk of developing cardiovascular events, and it was associated with higher mortality.
ABSTRACT
Background: Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods: We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results: We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions: In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.
ABSTRACT
Cisplatin-based chemotherapy has associated clinical disadvantages, such as high toxicity and resistance. Thus, the development of new antitumor metallodrugs able to overcome different clinical barriers is a public healthcare priority. Here, we studied the mechanism of action of the isomers trans and cis-[PtI2(isopropylamine)2] (I5 and I6, respectively) against gastrointestinal cancer cells. We demonstrate that I5 and I6 modulate mitochondrial metabolism, decreasing OXPHOS activity and negatively affecting ATP-linked oxygen consumption rate. Consequently, I5 and I6 generated Reactive Oxygen Species (ROS), provoking oxidative damage and eventually the induction of senescence. Thus, herein we propose a loop with three interconnected processes modulated by these iodido agents: (i) mitochondrial dysfunction and metabolic disruptions; (ii) ROS generation and oxidative damage; and (iii) cellular senescence. Functionally, I5 reduces cancer cell clonogenicity and tumor growth in a pancreatic xenograft model without systemic toxicity, highlighting a potential anticancer complex that warrants additional pre-clinical studies.
Subject(s)
Gastrointestinal Neoplasms , Platinum , Humans , Reactive Oxygen Species/metabolism , Cisplatin/pharmacology , Mitochondria/metabolism , Gastrointestinal Neoplasms/metabolismABSTRACT
The progression from prediabetes to type-2 diabetes depends on multiple pathophysiological, clinical, and epidemiological factors that generally overlap. Both insulin resistance and decreased insulin secretion are considered to be the main causes. The diagnosis and approach to the prediabetic patient are heterogeneous. There is no agreement on the diagnostic criteria to identify prediabetic subjects or the approach to those with insufficient responses to treatment, with respect to regression to normal glycemic values or the prevention of complications. The stratification of prediabetic patients, considering the indicators of impaired fasting glucose, impaired glucose tolerance, or HbA1c, can help to identify the sub-phenotypes of subjects at risk for T2DM. However, considering other associated risk factors, such as impaired lipid profiles, or risk scores, such as the Finnish Diabetes Risk Score, may improve classification. Nevertheless, we still do not have enough information regarding cardiovascular risk reduction. The sub-phenotyping of subjects with prediabetes may provide an opportunity to improve the screening and management of cardiometabolic risk in subjects with prediabetes.
ABSTRACT
Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.
Subject(s)
COVID-19 , Diabetes Mellitus , Thrombophilia , Thrombosis , Humans , COVID-19/complications , Post-Acute COVID-19 Syndrome , Pandemics , SARS-CoV-2 , Thrombophilia/diagnosis , Thrombophilia/drug therapy , Diabetes Mellitus/diagnosis , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , EndotheliumABSTRACT
BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.
Subject(s)
COVID-19 , Inflammasomes , Spike Glycoprotein, Coronavirus , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , COVID-19 Vaccines , NF-kappa B/metabolism , von Willebrand Factor , SARS-CoV-2 , Human Umbilical Vein Endothelial Cells/metabolism , Interleukin-1beta/metabolismABSTRACT
INTRODUCTION AND OBJECTIVES: Catheter-directed therapy (CDT) for acute pulmonary embolism (PE) is an emerging therapy that combines heterogeneous techniques. The aim of the study was to provide a nationwide contemporary snapshot of clinical practice and CDT-related outcomes. METHODS: This Investigator-initiated multicenter registry aimed to include consecutive patients with intermediate-high risk (IHR) or high-risk (HR), acute PE eligible for CDT. The primary outcome of the study was in-hospital all-cause death. RESULTS: A total of 253 patients were included, of whom 93 (36.8%) had HR-PE, and 160 (63.2%) had IHR-PE with a mean age of 62.3±15.1 years. Local thrombolysis was performed in 70.8% and aspiration thrombectomy in 51.8%, with 23.3% of patients receiving both. However, aspiration thrombectomy was favored in the HR-PE cohort (80.6% vs 35%; P<.001). Only 51 patients (20.2%) underwent CDT with specific PE devices. The success rate for CDT was 90.9% (98.1% of IHR-PE patients vs 78.5% of HR-PE patients, P<.001). In-hospital mortality was 15.5%, and was highly concentrated in the HR-PE patients (37.6%) and significantly lower in IHR-PE patients (2.5%), P<.001. Long-term (24-month) mortality was 40.2% in HR-PE patients vs 8.2% in IHR-PE patients (P<.001). CONCLUSIONS: Despite the high success rate for CDT, in-hospital mortality in HR-PE is still high (37.6%) compared with very low IHR-PE mortality (2.5%).
Subject(s)
Fibrinolytic Agents , Pulmonary Embolism , Humans , Middle Aged , Aged , Fibrinolytic Agents/therapeutic use , Thrombolytic Therapy/methods , Treatment Outcome , Pulmonary Embolism/therapy , Thrombectomy/methods , Catheters , Registries , Retrospective StudiesABSTRACT
AIMS: Abnormalities of mineral metabolism (MM) have been related to cardiovascular disorders. There are no reports on the prognostic role of MM after an acute coronary syndrome (ACS). We aim to assess the prognostic role of MM after an ACS. METHODS AND RESULTS: Plasma levels of components of MM [fibroblast growth factor 23 (FGF23), calcidiol, parathormone, klotho, and phosphate], high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured in 1190 patients at discharge from an ACS. The primary outcome was a combination of acute ischaemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Age was 61.7 ± 12.2 years, and 77.1% were men. Median follow-up was 5.44 (3.03-7.46) years. Two hundred and ninety-four patients developed the primary outcome. At multivariable analysis FGF23 (hazard ratio, HR 1.18 [1.08-1.29], P < 0.001), calcidiol (HR 0.86 [0.74-1.00], P = 0.046), previous coronary or cerebrovascular disease, and hypertension were independent predictors of the primary outcome. The predictive power of FGF23 was homogeneous across different subgroups of population. FGF23 (HR 1.45 [1.28-1.65], P < 0.001) and parathormone (HR 1.06 1.01-1.12]; P = 0.032) resulted as independent predictors of HF. FGF23 (HR 1.21 [1.07-1.37], P = 0.002) and calcidiol (HR 0.72 [0.54-0.97), P = 0.028) were independent predictors of death. No biomarker predicted acute ischaemic events. FGF23 predicted independently the primary outcome in patients with estimated glomerular filtration rate > 60 mL/min/1.73 m2 . CONCLUSIONS: FGF23 and other components of MM are independent predictors of HF and death after an ACS. This effect is homogeneous across different subgroups of population, and it is not limited to patients with chronic kidney disease.
Subject(s)
Acute Coronary Syndrome , Heart Failure , Aged , Female , Humans , Male , Middle Aged , Acute Coronary Syndrome/diagnosis , Calcifediol , Fibroblast Growth Factor-23 , Fibroblast Growth Factors , Parathyroid HormoneABSTRACT
Sodium-glucose cotransporter inhibitors (SGLT2i) have demonstrated a reduction in cardiovascular events in diabetes and heart failure (HF). The mechanisms underlying this benefit are not well known and data are contradictory. The purpose of this study is to analyse the effect of dapagliflozin on cardiac structure and function in patients with normal ejection fraction. Between October 2020 and October 2021, we consecutively included 31 diabetic patients without prior history of SGLT2i use. In all of them, dapagliflozin treatment was started. At inclusion and during six months of follow-up, different clinical, ECG, analytical, and echocardiographic (standard, 3D, and speckle tracking) variables were recorded. After a follow-up period of 6.6 months, an average reduction of 18 g (p = 0.028) in 3D-estimated left ventricle mass was observed. An increase in absolute left ventricle global longitudinal strain (LV-GLS) of 0.3 (p = 0.036) was observed, as well as an increase in isovolumetric relaxation time (IVRT) of 10.5 ms (p = 0.05). Moreover, dapagliflozin decreased the levels of plasma creatin-kinase (CK-MB) and atrial natriuretic peptide (ANP). In conclusion, our data show that the use of SGLT2i is associated with both structural (myocardial mass) and functional (IVRT, LV-GLS) cardiac improvements in a population of diabetic patients with normal ejection fraction.
ABSTRACT
To evaluate KL-6 levels in medium-term post-COVID and to compare them in three groups categorised by the severity of COVID-19, we conducted a real-world, retrospective, cohort study. Data from the COVID-19 episode and follow-up during the post-COVID phase were extracted from the COVID@HULP and POSTCOVID@HULP databases, respectively. For the post-COVID period we included demographics, medical history, symptoms, quality of life, physical activity, anxiety and depression status and laboratory results. Patients were categorised into three groups based on the severity of COVID-19: Group 1 (inpatient critical), Group 2 (inpatient non-critical) and Group 3 (hospitalised at home). KL-6 was measured during the follow-up of the three groups. In all, 802 patients were included (Group 1 = 59; Group 2 = 296; Group 3 = 447 patients). The median age was 59 years (48-70), and 362 (45.2%) were males. At admission, fibrinogen and ferritin levels were lower in Group 3 than in the other groups (p < 0.001). Follow-up data were obtained 124 days (97-149) after the diagnosis of COVID-19. The median levels of fibrinogen, ferritin and KL-6 at follow-up were 336 mg/dL (276-413), 80.5 ng/mL (36-174.3) and 326 U/mL (240.3-440.3), respectively. KL-6 levels were lower in Group 3 than in the other groups (298 U/mL (231.5-398) vs. 381.5 U/mL (304-511.8) (Group 1) and 372 U/mL (249-483) (Group 2) (p < 0.001)). KL-6 was associated with ferritin (p < 0.001), fibrinogen (p < 0.001), D-dimer (p < 0.001) and gamma-glutamyl transferase (p < 0.001). KL-6 levels are less elevated at medium-term post-COVID follow-up in patients with mild COVID-19 than in those with moderate or severe disease. KL-6 is associated with systemic inflammatory, hepatic enzyme and thrombosis biomarkers.
ABSTRACT
INTRODUCTION: Bariatric surgery is an efficient approach to rapidly reduce morbid obesity and associated comorbidities. However, approximately one-fourth of patients experience weight and comorbidity recurrence, and both obesity and bariatric surgery can lead to micronutrient deficiencies. Implementing a structured program of lifestyle modification (PLM) might enhance weight loss and improve micronutrient status. METHODOLOGY: A total of 121 severely obese patients underwent Roux-en-Y gastric bypass (RYGB). Among them, 71 adhered to a PLM involving dietary changes (low- and very-low-calorie Mediterranean diets) and physical exercises (aerobic and resistance training) both before and after surgery, while 50 patients followed a conventional protocol. Anthropometric measurements and serological parameter quantifications were conducted throughout the procedures. RESULTS: The obese study population, primarily female (76.9%), with an average age of 47.11 ± 9.68, and a body mass index (BMI) of 44.68 ± 5.08 kg/m2, underwent either RYGB with a PLM or a conventional procedure. Before surgery, the PLM group exhibited significant reductions in body weight (6.3%) and phosphoremia compared to the conventional protocol (0.78%). Post-RYGB, the PLM group demonstrated shortened in-hospital stays and further BMI reductions (-16.12 kg/m2) that persisted for up to 2 years. Furthermore, the PLM group experienced increased plasma vitamin D levels (14.79 ng/mL vs. 1.2 ng/mL) for up to 2 years, as well as elevated folic acid (1.52 vs. -0.29 ng/mL) and phosphorus (0.48 vs. 0.06 mg/dL) levels at 1 month and 1 year after intervention, respectively. Notably, these effects were independent of weight loss. CONCLUSIONS: Initiating a structured PLM from the early stages of patients' preparation for RYGB could enhance and extend the benefits of weight loss and positively impact micronutrient (vitamin D, phosphorus, and folic acid) status in obese patients.
Subject(s)
Bariatric Surgery , Obesity, Morbid , Trace Elements , Humans , Female , Adult , Middle Aged , Micronutrients , Life Style , Phosphorus , Folic Acid , Obesity, Morbid/surgerySubject(s)
Humans , Severe acute respiratory syndrome-related coronavirus/classification , Severe Acute Respiratory Syndrome/physiopathology , Severe Acute Respiratory Syndrome/virology , Hemodynamics/physiology , Severity of Illness Index , Hemodynamic Monitoring , Echocardiography/methods , Prospective StudiesABSTRACT
Type-2 diabetes (T2DM) and arterial hypertension (HTN) are major risk factors for heart failure. Importantly, these pathologies could induce synergetic alterations in the heart, and the discovery of key common molecular signaling may suggest new targets for therapy. Intraoperative cardiac biopsies were obtained from patients with coronary heart disease and preserved systolic function, with or without HTN and/or T2DM, who underwent coronary artery bypass grafting (CABG). Control (n = 5), HTN (n = 7), and HTN + T2DM (n = 7) samples were analysed by proteomics and bioinformatics. Additionally, cultured rat cardiomyocytes were used for the analysis (protein level and activation, mRNA expression, and bioenergetic performance) of key molecular mediators under stimulation of main components of HTN and T2DM (high glucose and/or fatty acids and angiotensin-II). As results, in cardiac biopsies, we found significant alterations of 677 proteins and after filtering for non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against the control. Interestingly, 81% of proteins in HTN-T2DM were distinct from HTN, while 95% from HTN were common with HTN-T2DM. In addition, 78 factors were differentially expressed in HTN-T2DM against HTN, predominantly downregulated proteins of mitochondrial respiration and lipid oxidation. Bioinformatic analyses suggested the implication of mTOR signaling and reduction of AMPK and PPARα activation, and regulation of PGC1α, fatty acid oxidation, and oxidative phosphorylation. In cultured cardiomyocytes, an excess of the palmitate activated mTORC1 complex and subsequent attenuation of PGC1α-PPARα transcription of ß-oxidation and mitochondrial electron chain factors affect mitochondrial/glycolytic ATP synthesis. Silencing of PGC1α further reduced total ATP and both mitochondrial and glycolytic ATP. Thus, the coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a marked downregulation of mitochondrial respiration and lipid metabolism and the mTORC1-PGC1α-PPARα axis might account as a target for therapeutical strategies.