CYLD-mediated DNA damage coordinates pathological cardiac hypertrophy via RIPK1-dependent signaling.

In the myocardium, collagen fibers provide a supporting framework for myocytes and blood vessels and act as lateral connections between muscle bundles. These functional properties of collagen serve to maintain tissue architecture and to coordinate the delivery of force generated by myocytes on the ventricular chamber. The accumulation of excess collagen is believed to be an important pathophysiological process that contributes to diastolic heart failure. Diastolic heart failure accounts for 30% to 50% of heart failure in clinical practice, and hypertensive disease is the major cause of this type of heart failure.1 The precise mechanisms responsible for excess fibrillar collagen accumulation in the pathological heart are poorly understood. Fibrosis of both the injured and noninjured myocardium2 indicates that humoral mechanisms are responsible for this process. In the failing heart, several humoral, autocrine, and paracrine systems are activated,3 suggesting that cross-talk between synergistic and opposing signaling pathways constitutes the predominant form of regulation under these conditions. Several factors have been identified as potentially important mediators of cardiac collagen production. In vitro studies of neonatal and adult rat cardiac fibroblasts have shown that angiotensin II (Ang II) directly stimulates cardiac fibroblast proliferation and collagen synthesis via Ang II type 1 (AT1) receptors.4 5 6 In this issue of Hypertension , Pathak et al7 provided evidence that a myocyte cofactor was an important mediator of Ang II–induced collagen type I and type III mRNA synthesis in a rat cell coculture model. This work, together with other studies, provides strong evidence that Ang II indirectly regulates cardiac fibroblast function via specific growth factors.8 9 10 11 12 13 14 15 16 17 18 19 20 21 Although the primary autocrine and paracrine mediators of Ang II effects on fibrillar collagen synthesis remain to be elucidated, principal candidates …

heart failure is the most important cause of death in the Western world, and numerous attempts have been undertaken to identify the origin of this disease. Cohn et al. ([1][1]) in 2000 defined cardiac remodeling leading to heart failure as “genome expression resulting in molecular, cellular and

How the heart senses increased biomechanic stress and converts this “input signal” to generalized downstream cardiac hypertrophy signaling paradigms remains an enigmatic but intriguing question in modern cardiovascular biology. Only recently have signaling molecules that can couple biomechanical stress to common pathways of cardiac hypertrophy been uncovered. Yeast-2-hybrid screens have identified several binding partners of sarcomeric proteins. These concerted actions revealed that especially the sarcomere Z-disc harbors key components that affect the activity of several notable kinases and phosphatase, including mitogen-activated protein kinases, protein kinases A and C, and calcineurin.1 Exemplary to this is the family of calsarcin proteins, which link the Z-disk protein α-actinin to calcineurin, a well-characterized Ca2+-responsive signaling molecule controlling activity of the transcription factor NFAT and both required and sufficient for cardiac hypertrophy after pleiotropic stimuli (Figure).2 However, interruption of the calcium overload typical for heart failure may not stop disease progression, and, therefore, Ca2+-independent signaling cascades might serve as useful targets to interfere with left ventricular (LV) remodeling on pressure overload or ischemia.3 Hypothetical signaling cascade linking Ang II signaling, cardiac mechanosensing at the sarcomere, and specific transcription factors in LV remodeling. Likewise, the giant sarcomeric protein titin is the starting point of a signaling complex where the zinc-finger protein nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres. In turn, p62 …

See related article, pages 113–123 Cardiac hypertrophy is often accompanied by cardiac remodeling characterized by loss of cardiac myocytes, interstitial fibroblasts, and collagen deposition, leading to decreased ventricular compliance and an increased risk for heart failure. The mortality for patients with heart failure is still high, although some improvements have been demonstrated in patients with systolic heart failure.1–3 To improve the therapeutic strategy for patients with heart failure, especially diastolic heart failure, further research and investigations to better understand the molecular and biochemical mechanism are needed. Serotonin (5-hydroxytryptamine [5-HT]) affects many physiological functions through the interaction with specific G-coupled membrane receptors, 5-HT receptors. There are 4 classes of 5-HT receptors (5-HT1/5, 5-HT2, 5-HT3, and 5-HT4/6/7).4 Serotonin, via the 5-HT2B receptor, regulates cardiac development and function.5 Transgenic mice with a 5-HT2B receptor gene ablation show embryonic and neonatal death caused by lack of trabeculae in the heart.6 5-HT2B receptors are essential for isoproterenol-induced cardiac hypertrophy, which involves the regulation of interleukin-6, interleukin-1β, and tumor necrosis factor-α cytokine production by cardiac fibroblasts.7 The 5-HT2B receptor has been shown functionally coupled to reactive oxygen species synthesis through NAD(P)H oxidase stimulation in neuronal cells8 and in angiotensin II and isoproterenol-induced cardiac hypertrophy.9 Recently, 5-HT2B receptor blockade has been shown to prevent the cardiac hypertrophy induced by angiotensin II or isoproterenol infusion.9 …

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.

Under acute or chronic stresses, the adult heart undergoes a remodeling process that involves cardiomyocyte hypertrophy accompanied by apoptosis, necrosis, and fibrosis that lead to impaired cardiac contractility. The role of endogenous regeneration in this process is currently under investigation. Sustained deleterious stimuli will lead to a decompensated form of hypertrophy often culminating in heart failure.1 This form of hypertrophy is often referred to as “maladaptive.” When dealing with hypertrophy, it appears important to distinguish between the term being used on the cellular and molecular level (enlargement of individual cardiomyocytes and re-expression of fetal/embryonic genes) and the organ level (increased heart weight, left ventricular wall thickness, and functional diastolic and systolic impairment). In our view, these processes are certainly linked but not identical. Hypertrophy on the organ levels summarizes several independent cellular and molecular processes (see below), where cardiomyocyte growth is not necessarily the most important. Independent of its origin, cardiac hypertrophy is associated with alterations in cardiac geometry, mass, architecture, and function controlled by a complex network of interconnected and abundant signal-transduction pathways.2 New signaling molecules are emerging as possible targets to specifically attenuate maladaptive hypertrophy. Pathological, stress-induced growth of cardiomyocytes was shown to depend on Wnt/β-catenin nuclear signaling rather than its adhesive function in cell adhesion. However, the specificity of the cell type and the molecular mechanisms governing the Wnt signaling–dependent changes are currently unknown.3 In this issue of the Hypertension , the study by Malekar et al4 provides new evidences concerning the …

Glucose Metabolism in Cardiac Hypertrophy and Heart Failure.

hanges in intracellular pH (pH i ) can produce marked effects on cardiac function, and, therefore, it is important that the cell possess mechanisms by which pH i is regulated, especially after intracellular acidosis associated with myocardial ischemia.The Na ϩ /H ϩ exchanger (NHE) and the Na ϩ /HCO 3 Ϫ symport represent the 2 major pathways by which alkalinization occurs in cardiac cells.The NHE not only regulates pH i but also cell volume and intracellular signaling in response to a variety of stimuli.

BackgroundCardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar‐associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling.Methods and ResultsMFAP4‐deficient (MFAP4−/−) and wild‐type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4−/− mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild‐type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild‐type‐sham and knockout‐sham mice.ConclusionsThese findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by impaired left ventricular (LV) diastolic function, with normal LV ejection fraction. Aortic valve stenosis can cause an HFpEF-like syndrome by inducing sustained pressure overload (PO) and cardiac remodeling, as cardiomyocyte (CM) hypertrophy and fibrotic matrix deposition. Recently, in vivo studies linked PO maladaptive myocardial changes and DNA damage response (DDR) activation: DDR-persistent activation contributes to mouse CM hypertrophy and inflammation, promoting tissue remodeling, and HF. Despite the wide acknowledgment of the pivotal role of the stromal compartment in the fibrotic response to PO, the possible effects of DDR-persistent activation in cardiac stromal cell (C-MSC) are still unknown. Finally, this novel mechanism was not verified in human samples. This study aims to unravel the effects of PO-induced DDR on human C-MSC phenotypes. Human LV septum samples collected from severe aortic stenosis with HFpEF-like syndrome patients undergoing aortic valve surgery and healthy controls (HCs) were used both for histological tissue analyses and C-MSC isolation. PO-induced mechanical stimuli were simulated in vitro by cyclic unidirectional stretch. Interestingly, HFpEF tissue samples revealed DNA damage both in CM and C-MSC. DDR-activation markers γH2AX, pCHK1, and pCHK2 were expressed at higher levels in HFpEF total tissue than in HC. Primary C-MSC isolated from HFpEF and HC subjects and expanded in vitro confirmed the increased γH2AX and phosphorylated checkpoint protein expression, suggesting a persistent DDR response, in parallel with a higher expression of pro-fibrotic and pro-inflammatory factors respect to HC cells, hinting to a DDR-driven remodeling of HFpEF C-MSC. Pressure overload was simulated in vitro, and persistent activation of the CHK1 axis was induced in response to in vitro mechanical stretching, which also increased C-MSC secreted pro-inflammatory and pro-fibrotic molecules. Finally, fibrosis markers were reverted by the treatment with a CHK1/ATR pathway inhibitor, confirming a cause-effect relationship. In conclusion we demonstrated that, in severe aortic stenosis with HFpEF-like syndrome patients, PO induces DDR-persistent activation not only in CM but also in C-MSC. In C-MSC, DDR activation leads to inflammation and fibrosis, which can be prevented by specific DDR targeting.

Chronic left ventricular (LV) failure or heart failure (HF) often progress to pulmonary remodeling and right ventricular (RV) hypertrophy even with optimal medical care. Cytotoxic CD8+ T cells play an important role in modulating virus infection and tissue injury by producing proinflammatory cytokines and cytolysis of the infected or injured cells. However, the role of CD8+ T cells in heart failure (HF)-induced lung remodeling and RV hypertrophy is unknown. To determine the role of CD8 T cells in modulating HF progression under preexisting HF conditions, wild type mice with existing LV failure produced by transverse aortic constriction (TAC) were randomized to depletion of cytotoxic CD8+ T cells, regulatory T cells (Tregs), or both by using specific blocking antibodies. The cardiac function, lung inflammation, fibrosis, vascular remodeling, and right ventricular remodeling were determined. As anticipated, LV failure caused lung inflammation and activation of pulmonary CD4+ T cells and CD8+ T cells. Interestingly, depletion of CD8+ T cells dramatically attenuated the increase of lung weight, lung inflammation, lung vascular remodeling, and RV hypertrophy in mice with existing LV failure. LV failure was associated with an increased ratio of activated T cells to Tregs, and Treg depletion exacerbated lung inflammation and the progression of LV failure. Treg depletion also exacerbated the lung CD4+ and CD8+ T cell infiltration, and the percentage of effector memory T cells (Tem) in HF mice. Depletion of CD8+ T cells was suffcient to rescued HF mice from the exacerbated lung inflammation and the progression of LV failure that was caused by Treg depletion. These findings demonstrate that CD8+ T cells play a critical role in promoting the transition from LV failure to lung remodeling and RV hypertrophy. NIH funding. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypertensive heart disease is a major contributor to cardiovascular morbidity and mortality, especially in African Americans, in whom LV hypertrophy is 2 to 3-fold more common in the general population as compared with whites.1 In the classic paradigm of hypertensive heart disease, concentric hypertrophy (a nondilated, thick-walled left ventricle typically with a normal left ventricular ejection fraction [LVEF]) is a common precursor to LV failure (an increased LV volume with reduced LVEF).2 Although molecular triggers of this transition from concentric hypertrophy to failure have been the subject of intense investigation, there are no previous large, longitudinal cohort studies in humans demonstrating that this progression occurs frequently. The transition from concentric LV hypertrophy to failure has been well demonstrated in animal models including the spontaneously hypertensive rat,3 or after aortic banding4 or transgenic manipulation,5 and also in humans with aortic stenosis6 or familial hypertrophic cardiomyopathy.7 Whether this paradigm faithfully represents the natural history of hypertensive heart disease is not yet known (Figure). An alternative paradigm is that the LV response to elevated blood pressure is either hypertrophy or failure, with transition between the 2 uncommon in the absence of an interval cardiac injury. Potential pathways in progression of hypertensive heart disease. Hypertension can lead to concentric left ventricular hypertrophy (LVH), characterized by nondilated, thick-walled left ventricle (arrow, top left). After “transition to failure,” the LV is dilated with reduced LVEF. Coronary artery disease often via MI is a common contributor to this transition (first horizontal arrow). Whether concentric LVH commonly leads to low EF in absence of an interval MI or significant coronary artery disease is uncertain (second horizontal arrow). If LVH is not common precursor to LV …

During the last few years, there has been an exponential rise in understanding functions and signal transduction mechanisms for angiotensin II (Ang II) type 2 receptors (AT2s).1 2 These studies are particularly relevant in view of the pivotal role of upregulation of AT2 in mediating tissue remodeling in many cardiovascular diseases, including vascular injury, atherosclerosis, cardiac hypertrophy, myocardial infarction, and congestive heart failure.1 Furthermore, Ang II type 1 receptor (AT1) antagonists, commonly used for treatment of hypertension and congestive heart failure, increase plasma levels of Ang II and upregulate AT2 expression. Under these conditions, the increase in AT2 is unopposed by AT1.1 3 Thus, understanding the role of AT2 in cardiovascular remodeling as well as the consequences of AT2 stimulation or inhibition during medical therapy is clinically important. AT2s only partially share the signaling mechanisms with AT1s and, in fact, counteract the signaling mechanisms activated by AT1s2 (Figure⇓). This negative nature of AT2 signaling has made the elucidation of its function more difficult than that of AT1. However, recent studies on the cardiovascular functions of AT2 seem to have reached a consensus: AT2s exert growth inhibitory effects either by suppressing cell proliferation and hypertrophy4 5 or by stimulating apoptosis.1 2 6 These actions alone may not explain the diverse cardiovascular phenomena attributed to AT2, resulting in unanswered questions. Why are AT2s abundant in growing fetal tissues? Why are AT2s abundant in tissues undergoing remodeling? Recently, an elegant genetic study has provided an answer to some of these questions, showing that an important function of AT2 in the fetal kidney is to stimulate apoptosis. Targeted …

Increased glycolytic metabolism in cardiac hypertrophy and congestive failure

### 24178 ### MAVS Mediates Protection against Myocardial Ischemic Injury with Hydrogen Sulfide David Durrant, Adolfo G Mauro, Juan Valle Raleigh, Anindita Das, Jun He, Khoa Nguyen, Stefano Toldo, Antonio Abbate, Fadi N Salloum; Virginia Commonwealth Univ, Richmond, VA Background : Hydrogen sulfide (H2S) has been shown to protect against myocardial ischemic and inflammatory injury in part by preserving mitochondrial integrity. Since mitochondrial antiviral signaling (MAVS) protein has been implicated in attenuating Bax-mediated cytochrome c release from mitochondria caused by oxidative stress or ischemia, we sought to determine whether MAVS mediates the cardioprotective effects of H2S. Methods and Results : After baseline echocardiography, adult male wild type (WT) or MAVS KO mice underwent myocardial infarction (MI) by coronary artery ligation for 30 min. followed by 24 h reperfusion. Mice were pretreated with Na2S (100 μg/kg; ip ) or saline 1 h before MI. Infarct size, measured with TTC staining, was reduced and LV fractional shortening (FS) was preserved with Na2S at 24h post MI in WT mice as compared to saline-treated mice, but not in MAVS KO mice (Figs. A and B). The risk area was not different between the groups. Western blot analysis revealed a significant decline in myocardial MAVS expression at 24h post MI, which was preserved with Na2S (Fig. C). Another subset of mice was subjected to permanent coronary artery occlusion and treated with Na2S or saline daily for 28 days. LVFS decreased significantly at 28 days post-MI in the saline group, but was significantly preserved with Na2S (Fig. D). Moreover, LV infarct scar size, assessed by trichrome staining, was smaller in Na2S group (22.4 ± 2.7%) as compared to control (33.5 ± 2.1%, P<0.05). Survival rate was 2 fold higher with Na2S compared to saline (P<0.05). Western blot analysis confirmed a significant …